Full text data of MRE11A
MRE11A
(HNGS1, MRE11)
[Confidence: low (only semi-automatic identification from reviews)]
Double-strand break repair protein MRE11A (Meiotic recombination 11 homolog 1; MRE11 homolog 1; Meiotic recombination 11 homolog A; MRE11 homolog A)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Double-strand break repair protein MRE11A (Meiotic recombination 11 homolog 1; MRE11 homolog 1; Meiotic recombination 11 homolog A; MRE11 homolog A)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P49959
ID MRE11_HUMAN Reviewed; 708 AA.
AC P49959; O43475;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 26-SEP-2001, sequence version 3.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Double-strand break repair protein MRE11A;
DE AltName: Full=Meiotic recombination 11 homolog 1;
DE Short=MRE11 homolog 1;
DE AltName: Full=Meiotic recombination 11 homolog A;
DE Short=MRE11 homolog A;
GN Name=MRE11A; Synonyms=HNGS1, MRE11;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=8530104; DOI=10.1006/geno.1995.1217;
RA Petrini J.H.J., Walsh M.E., Dimare C., Chen X.-N., Korenberg J.R.,
RA Weaver D.T.;
RT "Isolation and characterization of the human MRE11 homologue.";
RL Genomics 29:80-86(1995).
RN [2]
RP SEQUENCE REVISION TO C-TERMINUS.
RA Petrini J.H.J., Walsh M.E., Dimare C., Chen X.-N., Korenberg J.R.,
RA Weaver D.T.;
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Chamankhah M., Wei Y., Xiao W.;
RT "Molecular cloning and functional characterization of hNGS1, a yeast
RT and human MRE11 homolog.";
RL Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9651580; DOI=10.1016/S1097-2765(00)80097-0;
RA Paull T.T., Gellert M.;
RT "The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA
RT double-strand breaks.";
RL Mol. Cell 1:969-979(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=11371508; DOI=10.1093/hmg/10.11.1155;
RA Pitts S.A., Kullar H.S., Stankovic T., Stewart G.S., Last J.I.K.,
RA Bedenham T., Armstrong S.J., Piane M., Chessa L., Taylor A.M.R.,
RA Byrd P.J.;
RT "hMRE11: genomic structure and a null mutation identified in a
RT transcript protected from nonsense-mediated mRNA decay.";
RL Hum. Mol. Genet. 10:1155-1162(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-468 AND VAL-698.
RG NIEHS SNPs program;
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH DCLRE1C.
RX PubMed=15456891; DOI=10.1128/MCB.24.20.9207-9220.2004;
RA Zhang X., Succi J., Feng Z., Prithivirajsingh S., Story M.D.,
RA Legerski R.J.;
RT "Artemis is a phosphorylation target of ATM and ATR and is involved in
RT the G2/M DNA damage checkpoint response.";
RL Mol. Cell. Biol. 24:9207-9220(2004).
RN [9]
RP INTERACTION WITH DCLRE1C.
RX PubMed=15723659; DOI=10.1111/j.1349-7006.2005.00019.x;
RA Chen L., Morio T., Minegishi Y., Nakada S., Nagasawa M., Komatsu K.,
RA Chessa L., Villa A., Lecis D., Delia D., Mizutani S.;
RT "Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in
RT response to DNA damage.";
RL Cancer Sci. 96:134-141(2005).
RN [10]
RP INTERACTION WITH ATF2, AND SUBCELLULAR LOCATION.
RX PubMed=15916964; DOI=10.1016/j.molcel.2005.04.015;
RA Bhoumik A., Takahashi S., Breitweiser W., Shiloh Y., Jones N.,
RA Ronai Z.;
RT "ATM-dependent phosphorylation of ATF2 is required for the DNA damage
RT response.";
RL Mol. Cell 18:577-587(2005).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [13]
RP INTERACTION WITH DCLRE1B.
RX PubMed=18469862; DOI=10.1038/onc.2008.139;
RA Bae J.B., Mukhopadhyay S.S., Liu L., Zhang N., Tan J., Akhter S.,
RA Liu X., Shen X., Li L., Legerski R.J.;
RT "Snm1B/Apollo mediates replication fork collapse and S Phase
RT checkpoint activation in response to DNA interstrand cross-links.";
RL Oncogene 27:5045-5056(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-649; SER-688; SER-689
RP AND SER-701, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-649; SER-688 AND
RP SER-689, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688 AND SER-689, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688 AND SER-689, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [20]
RP INVOLVEMENT IN NPHP-RC.
RX PubMed=22863007; DOI=10.1016/j.cell.2012.06.028;
RA Chaki M., Airik R., Ghosh A.K., Giles R.H., Chen R., Slaats G.G.,
RA Wang H., Hurd T.W., Zhou W., Cluckey A., Gee H.Y., Ramaswami G.,
RA Hong C.J., Hamilton B.A., Cervenka I., Ganji R.S., Bryja V.,
RA Arts H.H., van Reeuwijk J., Oud M.M., Letteboer S.J., Roepman R.,
RA Husson H., Ibraghimov-Beskrovnaya O., Yasunaga T., Walz G., Eley L.,
RA Sayer J.A., Schermer B., Liebau M.C., Benzing T., Le Corre S.,
RA Drummond I., Janssen S., Allen S.J., Natarajan S., O'Toole J.F.,
RA Attanasio M., Saunier S., Antignac C., Koenekoop R.K., Ren H.,
RA Lopez I., Nayir A., Stoetzel C., Dollfus H., Massoudi R.,
RA Gleeson J.G., Andreoli S.P., Doherty D.G., Lindstrad A., Golzio C.,
RA Katsanis N., Pape L., Abboud E.B., Al-Rajhi A.A., Lewis R.A.,
RA Omran H., Lee E.Y., Wang S., Sekiguchi J.M., Saunders R.,
RA Johnson C.A., Garner E., Vanselow K., Andersen J.S., Shlomai J.,
RA Nurnberg G., Nurnberg P., Levy S., Smogorzewska A., Otto E.A.,
RA Hildebrandt F.;
RT "Exome capture reveals ZNF423 and CEP164 mutations, linking renal
RT ciliopathies to DNA damage response signaling.";
RL Cell 150:533-548(2012).
RN [21]
RP VARIANT ATLD SER-117.
RX PubMed=10612394; DOI=10.1016/S0092-8674(00)81547-0;
RA Stewart G.S., Maser R.S., Stankovic T., Bressan D.A., Kaplan M.I.,
RA Jaspers N.G.J., Raams A., Byrd P.J., Petrini J.H.J., Taylor A.M.R.;
RT "The DNA double-strand break repair gene hMRE11 is mutated in
RT individuals with an ataxia-telangiectasia-like disorder.";
RL Cell 99:577-587(1999).
RN [22]
RP VARIANTS CANCER CYS-104; HIS-503 AND GLN-572.
RX PubMed=11196167;
RA Fukuda T., Sumiyoshi T., Takahashi M., Kataoka T., Asahara T.,
RA Inui H., Watatani M., Yasutomi M., Kamada N., Miyagawa K.;
RT "Alterations of the double-strand break repair gene MRE11 in cancer.";
RL Cancer Res. 61:23-26(2001).
RN [23]
RP VARIANT OVARIAN CANCER TRP-305.
RX PubMed=14684699; DOI=10.1136/jmg.40.12.e131;
RA Heikkinen K., Karppinen S.-M., Soini Y., Maekinen M., Winqvist R.;
RT "Mutation screening of Mre11 complex genes: indication of RAD50
RT involvement in breast and ovarian cancer susceptibility.";
RL J. Med. Genet. 40:E131-E131(2003).
RN [24]
RP VARIANTS [LARGE SCALE ANALYSIS] CYS-237 AND TYR-302.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Component of the MRN complex, which plays a central role
CC in double-strand break (DSB) repair, DNA recombination,
CC maintenance of telomere integrity and meiosis. The complex
CC possesses single-strand endonuclease activity and double-strand-
CC specific 3'-5' exonuclease activity, which are provided by MRE11A.
CC RAD50 may be required to bind DNA ends and hold them in close
CC proximity. This could facilitate searches for short or long
CC regions of sequence homology in the recombining DNA templates, and
CC may also stimulate the activity of DNA ligases and/or restrict the
CC nuclease activity of MRE11A to prevent nucleolytic degradation
CC past a given point. The complex may also be required for DNA
CC damage signaling via activation of the ATM kinase. In telomeres
CC the MRN complex may modulate t-loop formation.
CC -!- COFACTOR: Manganese (By similarity).
CC -!- SUBUNIT: Component of the MRN complex composed of two heterodimers
CC RAD50/MRE11A associated with a single NBN. Component of the BASC
CC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM,
CC RAD50, MRE11A and NBN (By similarity). Interacts with
CC DCLRE1C/Artemis and DCLRE1B/Apollo. Interacts with ATF2.
CC -!- INTERACTION:
CC Q9BXW9:FANCD2; NbExp=6; IntAct=EBI-396513, EBI-359343;
CC P16104:H2AFX; NbExp=4; IntAct=EBI-396513, EBI-494830;
CC O60934:NBN; NbExp=2; IntAct=EBI-396513, EBI-494844;
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). Note=Localizes to
CC discrete nuclear foci after treatment with genotoxic agents (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P49959-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P49959-2; Sequence=VSP_003262;
CC -!- DISEASE: Ataxia-telangiectasia-like disorder (ATLD) [MIM:604391]:
CC A rare disorder characterized by progressive cerebellar ataxia,
CC dysarthria, abnormal eye movements, and absence of telangiectasia.
CC ATLD patients show normal levels of total IgG, IgA and IgM,
CC although there may be reduced levels of specific functional
CC antibodies. At the cellular level, ATLD exhibits hypersensitivity
CC to ionizing radiation and radioresistant DNA synthesis. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Note=Defects in MRE11A can be a cause of
CC nephronophthisis-related ciliopathies (NPHP-RC), a group of
CC recessive diseases that affect kidney, retina and brain. A
CC homozygous truncating mutation MRE11A has been found in patients
CC with cerebellar vermis hypoplasia, ataxia and dysarthria.
CC -!- MISCELLANEOUS: In case of infection by adenovirus E4, the MRN
CC complex is inactivated and degraded by viral oncoproteins, thereby
CC preventing concatenation of viral genomes in infected cells.
CC -!- SIMILARITY: Belongs to the MRE11/RAD32 family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MRE11ID247.html";
CC -!- WEB RESOURCE: Name=MRE11base; Note=MRE11A mutation db;
CC URL="http://bioinf.uta.fi/MRE11Abase/";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mre11a/";
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DR EMBL; U37359; AAC78721.1; -; mRNA.
DR EMBL; AF022778; AAD10197.1; -; mRNA.
DR EMBL; AF073362; AAC36249.1; -; mRNA.
DR EMBL; AF303395; AAK18790.1; -; Genomic_DNA.
DR EMBL; AF303379; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303380; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303381; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303382; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303383; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303384; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303385; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303386; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303387; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303388; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303389; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303390; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303391; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303392; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303393; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303394; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AY584241; AAS79320.1; -; Genomic_DNA.
DR EMBL; BC063458; AAH63458.1; -; mRNA.
DR RefSeq; NP_005581.2; NM_005590.3.
DR RefSeq; NP_005582.1; NM_005591.3.
DR RefSeq; XP_005274064.1; XM_005274007.1.
DR UniGene; Hs.192649; -.
DR PDB; 3T1I; X-ray; 3.00 A; A/B/C/D=1-411.
DR PDBsum; 3T1I; -.
DR ProteinModelPortal; P49959; -.
DR SMR; P49959; 8-400.
DR DIP; DIP-33238N; -.
DR IntAct; P49959; 16.
DR MINT; MINT-131851; -.
DR STRING; 9606.ENSP00000325863; -.
DR PhosphoSite; P49959; -.
DR DMDM; 17380137; -.
DR PaxDb; P49959; -.
DR PRIDE; P49959; -.
DR DNASU; 4361; -.
DR Ensembl; ENST00000323929; ENSP00000325863; ENSG00000020922.
DR Ensembl; ENST00000323977; ENSP00000326094; ENSG00000020922.
DR GeneID; 4361; -.
DR KEGG; hsa:4361; -.
DR UCSC; uc001peu.2; human.
DR CTD; 4361; -.
DR GeneCards; GC11M094150; -.
DR HGNC; HGNC:7230; MRE11A.
DR HPA; CAB004081; -.
DR HPA; HPA002691; -.
DR MIM; 600814; gene.
DR MIM; 604391; phenotype.
DR neXtProt; NX_P49959; -.
DR Orphanet; 251347; Ataxia-telangiectasia-like disorder.
DR Orphanet; 145; Hereditary breast and ovarian cancer syndrome.
DR PharmGKB; PA30934; -.
DR eggNOG; COG0420; -.
DR HOGENOM; HOG000216581; -.
DR HOVERGEN; HBG052508; -.
DR InParanoid; P49959; -.
DR KO; K10865; -.
DR OrthoDB; EOG7VB2F1; -.
DR PhylomeDB; P49959; -.
DR Reactome; REACT_111183; Meiosis.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_216; DNA Repair.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; MRE11A; human.
DR GeneWiki; MRE11A; -.
DR GenomeRNAi; 4361; -.
DR NextBio; 17163; -.
DR PMAP-CutDB; P49959; -.
DR PRO; PR:P49959; -.
DR ArrayExpress; P49959; -.
DR Bgee; P49959; -.
DR CleanEx; HS_MRE11A; -.
DR Genevestigator; P49959; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030870; C:Mre11 complex; NAS:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0008408; F:3'-5' exonuclease activity; TAS:ProtInc.
DR GO; GO:0003690; F:double-stranded DNA binding; TAS:ProtInc.
DR GO; GO:0030145; F:manganese ion binding; IEA:InterPro.
DR GO; GO:0000014; F:single-stranded DNA endodeoxyribonuclease activity; TAS:ProtInc.
DR GO; GO:0000075; P:cell cycle checkpoint; IEA:Ensembl.
DR GO; GO:0008283; P:cell proliferation; IEA:Ensembl.
DR GO; GO:0032508; P:DNA duplex unwinding; IMP:BHF-UCL.
DR GO; GO:0000724; P:double-strand break repair via homologous recombination; TAS:Reactome.
DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0032876; P:negative regulation of DNA endoreduplication; IMP:BHF-UCL.
DR GO; GO:0033674; P:positive regulation of kinase activity; IDA:BHF-UCL.
DR GO; GO:0031954; P:positive regulation of protein autophosphorylation; IDA:BHF-UCL.
DR GO; GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0007131; P:reciprocal meiotic recombination; TAS:ProtInc.
DR GO; GO:0000019; P:regulation of mitotic recombination; TAS:ProtInc.
DR GO; GO:0007062; P:sister chromatid cohesion; IMP:BHF-UCL.
DR GO; GO:0007129; P:synapsis; IEA:Ensembl.
DR GO; GO:0007004; P:telomere maintenance via telomerase; TAS:ProtInc.
DR InterPro; IPR003701; DNA_repair_Mre11.
DR InterPro; IPR007281; Mre11_DNA-bd.
DR InterPro; IPR004843; PEstase_dom.
DR PANTHER; PTHR10139; PTHR10139; 1.
DR Pfam; PF00149; Metallophos; 1.
DR Pfam; PF04152; Mre11_DNA_bind; 1.
DR PIRSF; PIRSF000882; DSB_repair_MRE11; 1.
DR TIGRFAMs; TIGR00583; mre11; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Ciliopathy;
KW Complete proteome; Disease mutation; DNA damage; DNA repair;
KW Endonuclease; Exonuclease; Hydrolase; Manganese; Meiosis; Nuclease;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 708 Double-strand break repair protein
FT MRE11A.
FT /FTId=PRO_0000138672.
FT ACT_SITE 129 129 Proton donor (By similarity).
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 2 2 Phosphoserine (By similarity).
FT MOD_RES 649 649 Phosphoserine.
FT MOD_RES 688 688 Phosphoserine.
FT MOD_RES 689 689 Phosphoserine.
FT MOD_RES 701 701 Phosphoserine.
FT VAR_SEQ 595 622 Missing (in isoform 2).
FT /FTId=VSP_003262.
FT VARIANT 104 104 S -> C (in cancer).
FT /FTId=VAR_011625.
FT VARIANT 117 117 N -> S (in ATLD).
FT /FTId=VAR_008513.
FT VARIANT 157 157 M -> V (in dbSNP:rs147771140).
FT /FTId=VAR_011626.
FT VARIANT 237 237 F -> C (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036416.
FT VARIANT 302 302 H -> Y (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036417.
FT VARIANT 305 305 R -> W (in ovarian cancer).
FT /FTId=VAR_025528.
FT VARIANT 468 468 D -> G (in dbSNP:rs1805367).
FT /FTId=VAR_019288.
FT VARIANT 503 503 R -> H (in cancer).
FT /FTId=VAR_011627.
FT VARIANT 572 572 R -> Q (in cancer; dbSNP:rs200085146).
FT /FTId=VAR_011628.
FT VARIANT 698 698 M -> V (in dbSNP:rs1805362).
FT /FTId=VAR_019289.
FT CONFLICT 31 31 V -> A (in Ref. 1; AAC78721).
FT HELIX 9 11
FT STRAND 12 18
FT TURN 24 26
FT TURN 30 34
FT HELIX 35 49
FT STRAND 53 57
FT STRAND 62 66
FT HELIX 69 83
FT STRAND 122 124
FT STRAND 128 130
FT TURN 134 137
FT HELIX 140 147
FT STRAND 149 152
FT STRAND 162 164
FT STRAND 167 171
FT STRAND 174 181
FT HELIX 186 194
FT STRAND 198 200
FT HELIX 207 209
FT STRAND 210 216
FT STRAND 223 228
FT HELIX 231 233
FT STRAND 240 243
FT STRAND 250 255
FT TURN 257 259
FT STRAND 262 265
FT HELIX 276 279
FT STRAND 283 290
FT STRAND 293 300
FT STRAND 302 304
FT STRAND 307 313
FT HELIX 314 316
FT TURN 318 320
FT HELIX 328 350
FT TURN 351 353
FT STRAND 355 357
FT STRAND 362 368
FT TURN 370 372
FT HELIX 379 385
FT TURN 386 388
FT STRAND 392 399
SQ SEQUENCE 708 AA; 80593 MW; D94ABFBDDF6106AD CRC64;
MSTADALDDE NTFKILVATD IHLGFMEKDA VRGNDTFVTL DEILRLAQEN EVDFILLGGD
LFHENKPSRK TLHTCLELLR KYCMGDRPVQ FEILSDQSVN FGFSKFPWVN YQDGNLNISI
PVFSIHGNHD DPTGADALCA LDILSCAGFV NHFGRSMSVE KIDISPVLLQ KGSTKIALYG
LGSIPDERLY RMFVNKKVTM LRPKEDENSW FNLFVIHQNR SKHGSTNFIP EQFLDDFIDL
VIWGHEHECK IAPTKNEQQL FYISQPGSSV VTSLSPGEAV KKHVGLLRIK GRKMNMHKIP
LHTVRQFFME DIVLANHPDI FNPDNPKVTQ AIQSFCLEKI EEMLENAERE RLGNSHQPEK
PLVRLRVDYS GGFEPFSVLR FSQKFVDRVA NPKDIIHFFR HREQKEKTGE EINFGKLITK
PSEGTTLRVE DLVKQYFQTA EKNVQLSLLT ERGMGEAVQE FVDKEEKDAI EELVKYQLEK
TQRFLKERHI DALEDKIDEE VRRFRETRQK NTNEEDDEVR EAMTRARALR SQSEESASAF
SADDLMSIDL AEQMANDSDD SISAATNKGR GRGRGRRGGR GQNSASRGGS QRGRADTGLE
TSTRSRNSKT AVSASRNMSI IDAFKSTRQQ PSRNVTTKNY SEVIEVDESD VEEDIFPTTS
KTDQRWSSTS SSKIMSQSQV SKGVDFESSE DDDDDPFMNT SSLRRNRR
//
ID MRE11_HUMAN Reviewed; 708 AA.
AC P49959; O43475;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 26-SEP-2001, sequence version 3.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Double-strand break repair protein MRE11A;
DE AltName: Full=Meiotic recombination 11 homolog 1;
DE Short=MRE11 homolog 1;
DE AltName: Full=Meiotic recombination 11 homolog A;
DE Short=MRE11 homolog A;
GN Name=MRE11A; Synonyms=HNGS1, MRE11;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=8530104; DOI=10.1006/geno.1995.1217;
RA Petrini J.H.J., Walsh M.E., Dimare C., Chen X.-N., Korenberg J.R.,
RA Weaver D.T.;
RT "Isolation and characterization of the human MRE11 homologue.";
RL Genomics 29:80-86(1995).
RN [2]
RP SEQUENCE REVISION TO C-TERMINUS.
RA Petrini J.H.J., Walsh M.E., Dimare C., Chen X.-N., Korenberg J.R.,
RA Weaver D.T.;
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Chamankhah M., Wei Y., Xiao W.;
RT "Molecular cloning and functional characterization of hNGS1, a yeast
RT and human MRE11 homolog.";
RL Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9651580; DOI=10.1016/S1097-2765(00)80097-0;
RA Paull T.T., Gellert M.;
RT "The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA
RT double-strand breaks.";
RL Mol. Cell 1:969-979(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=11371508; DOI=10.1093/hmg/10.11.1155;
RA Pitts S.A., Kullar H.S., Stankovic T., Stewart G.S., Last J.I.K.,
RA Bedenham T., Armstrong S.J., Piane M., Chessa L., Taylor A.M.R.,
RA Byrd P.J.;
RT "hMRE11: genomic structure and a null mutation identified in a
RT transcript protected from nonsense-mediated mRNA decay.";
RL Hum. Mol. Genet. 10:1155-1162(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-468 AND VAL-698.
RG NIEHS SNPs program;
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH DCLRE1C.
RX PubMed=15456891; DOI=10.1128/MCB.24.20.9207-9220.2004;
RA Zhang X., Succi J., Feng Z., Prithivirajsingh S., Story M.D.,
RA Legerski R.J.;
RT "Artemis is a phosphorylation target of ATM and ATR and is involved in
RT the G2/M DNA damage checkpoint response.";
RL Mol. Cell. Biol. 24:9207-9220(2004).
RN [9]
RP INTERACTION WITH DCLRE1C.
RX PubMed=15723659; DOI=10.1111/j.1349-7006.2005.00019.x;
RA Chen L., Morio T., Minegishi Y., Nakada S., Nagasawa M., Komatsu K.,
RA Chessa L., Villa A., Lecis D., Delia D., Mizutani S.;
RT "Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in
RT response to DNA damage.";
RL Cancer Sci. 96:134-141(2005).
RN [10]
RP INTERACTION WITH ATF2, AND SUBCELLULAR LOCATION.
RX PubMed=15916964; DOI=10.1016/j.molcel.2005.04.015;
RA Bhoumik A., Takahashi S., Breitweiser W., Shiloh Y., Jones N.,
RA Ronai Z.;
RT "ATM-dependent phosphorylation of ATF2 is required for the DNA damage
RT response.";
RL Mol. Cell 18:577-587(2005).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [13]
RP INTERACTION WITH DCLRE1B.
RX PubMed=18469862; DOI=10.1038/onc.2008.139;
RA Bae J.B., Mukhopadhyay S.S., Liu L., Zhang N., Tan J., Akhter S.,
RA Liu X., Shen X., Li L., Legerski R.J.;
RT "Snm1B/Apollo mediates replication fork collapse and S Phase
RT checkpoint activation in response to DNA interstrand cross-links.";
RL Oncogene 27:5045-5056(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-649; SER-688; SER-689
RP AND SER-701, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-649; SER-688 AND
RP SER-689, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688 AND SER-689, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688 AND SER-689, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [20]
RP INVOLVEMENT IN NPHP-RC.
RX PubMed=22863007; DOI=10.1016/j.cell.2012.06.028;
RA Chaki M., Airik R., Ghosh A.K., Giles R.H., Chen R., Slaats G.G.,
RA Wang H., Hurd T.W., Zhou W., Cluckey A., Gee H.Y., Ramaswami G.,
RA Hong C.J., Hamilton B.A., Cervenka I., Ganji R.S., Bryja V.,
RA Arts H.H., van Reeuwijk J., Oud M.M., Letteboer S.J., Roepman R.,
RA Husson H., Ibraghimov-Beskrovnaya O., Yasunaga T., Walz G., Eley L.,
RA Sayer J.A., Schermer B., Liebau M.C., Benzing T., Le Corre S.,
RA Drummond I., Janssen S., Allen S.J., Natarajan S., O'Toole J.F.,
RA Attanasio M., Saunier S., Antignac C., Koenekoop R.K., Ren H.,
RA Lopez I., Nayir A., Stoetzel C., Dollfus H., Massoudi R.,
RA Gleeson J.G., Andreoli S.P., Doherty D.G., Lindstrad A., Golzio C.,
RA Katsanis N., Pape L., Abboud E.B., Al-Rajhi A.A., Lewis R.A.,
RA Omran H., Lee E.Y., Wang S., Sekiguchi J.M., Saunders R.,
RA Johnson C.A., Garner E., Vanselow K., Andersen J.S., Shlomai J.,
RA Nurnberg G., Nurnberg P., Levy S., Smogorzewska A., Otto E.A.,
RA Hildebrandt F.;
RT "Exome capture reveals ZNF423 and CEP164 mutations, linking renal
RT ciliopathies to DNA damage response signaling.";
RL Cell 150:533-548(2012).
RN [21]
RP VARIANT ATLD SER-117.
RX PubMed=10612394; DOI=10.1016/S0092-8674(00)81547-0;
RA Stewart G.S., Maser R.S., Stankovic T., Bressan D.A., Kaplan M.I.,
RA Jaspers N.G.J., Raams A., Byrd P.J., Petrini J.H.J., Taylor A.M.R.;
RT "The DNA double-strand break repair gene hMRE11 is mutated in
RT individuals with an ataxia-telangiectasia-like disorder.";
RL Cell 99:577-587(1999).
RN [22]
RP VARIANTS CANCER CYS-104; HIS-503 AND GLN-572.
RX PubMed=11196167;
RA Fukuda T., Sumiyoshi T., Takahashi M., Kataoka T., Asahara T.,
RA Inui H., Watatani M., Yasutomi M., Kamada N., Miyagawa K.;
RT "Alterations of the double-strand break repair gene MRE11 in cancer.";
RL Cancer Res. 61:23-26(2001).
RN [23]
RP VARIANT OVARIAN CANCER TRP-305.
RX PubMed=14684699; DOI=10.1136/jmg.40.12.e131;
RA Heikkinen K., Karppinen S.-M., Soini Y., Maekinen M., Winqvist R.;
RT "Mutation screening of Mre11 complex genes: indication of RAD50
RT involvement in breast and ovarian cancer susceptibility.";
RL J. Med. Genet. 40:E131-E131(2003).
RN [24]
RP VARIANTS [LARGE SCALE ANALYSIS] CYS-237 AND TYR-302.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Component of the MRN complex, which plays a central role
CC in double-strand break (DSB) repair, DNA recombination,
CC maintenance of telomere integrity and meiosis. The complex
CC possesses single-strand endonuclease activity and double-strand-
CC specific 3'-5' exonuclease activity, which are provided by MRE11A.
CC RAD50 may be required to bind DNA ends and hold them in close
CC proximity. This could facilitate searches for short or long
CC regions of sequence homology in the recombining DNA templates, and
CC may also stimulate the activity of DNA ligases and/or restrict the
CC nuclease activity of MRE11A to prevent nucleolytic degradation
CC past a given point. The complex may also be required for DNA
CC damage signaling via activation of the ATM kinase. In telomeres
CC the MRN complex may modulate t-loop formation.
CC -!- COFACTOR: Manganese (By similarity).
CC -!- SUBUNIT: Component of the MRN complex composed of two heterodimers
CC RAD50/MRE11A associated with a single NBN. Component of the BASC
CC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM,
CC RAD50, MRE11A and NBN (By similarity). Interacts with
CC DCLRE1C/Artemis and DCLRE1B/Apollo. Interacts with ATF2.
CC -!- INTERACTION:
CC Q9BXW9:FANCD2; NbExp=6; IntAct=EBI-396513, EBI-359343;
CC P16104:H2AFX; NbExp=4; IntAct=EBI-396513, EBI-494830;
CC O60934:NBN; NbExp=2; IntAct=EBI-396513, EBI-494844;
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). Note=Localizes to
CC discrete nuclear foci after treatment with genotoxic agents (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P49959-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P49959-2; Sequence=VSP_003262;
CC -!- DISEASE: Ataxia-telangiectasia-like disorder (ATLD) [MIM:604391]:
CC A rare disorder characterized by progressive cerebellar ataxia,
CC dysarthria, abnormal eye movements, and absence of telangiectasia.
CC ATLD patients show normal levels of total IgG, IgA and IgM,
CC although there may be reduced levels of specific functional
CC antibodies. At the cellular level, ATLD exhibits hypersensitivity
CC to ionizing radiation and radioresistant DNA synthesis. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Note=Defects in MRE11A can be a cause of
CC nephronophthisis-related ciliopathies (NPHP-RC), a group of
CC recessive diseases that affect kidney, retina and brain. A
CC homozygous truncating mutation MRE11A has been found in patients
CC with cerebellar vermis hypoplasia, ataxia and dysarthria.
CC -!- MISCELLANEOUS: In case of infection by adenovirus E4, the MRN
CC complex is inactivated and degraded by viral oncoproteins, thereby
CC preventing concatenation of viral genomes in infected cells.
CC -!- SIMILARITY: Belongs to the MRE11/RAD32 family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MRE11ID247.html";
CC -!- WEB RESOURCE: Name=MRE11base; Note=MRE11A mutation db;
CC URL="http://bioinf.uta.fi/MRE11Abase/";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mre11a/";
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DR EMBL; U37359; AAC78721.1; -; mRNA.
DR EMBL; AF022778; AAD10197.1; -; mRNA.
DR EMBL; AF073362; AAC36249.1; -; mRNA.
DR EMBL; AF303395; AAK18790.1; -; Genomic_DNA.
DR EMBL; AF303379; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303380; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303381; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303382; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303383; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303384; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303385; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303386; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303387; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303388; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303389; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303390; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303391; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303392; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303393; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AF303394; AAK18790.1; JOINED; Genomic_DNA.
DR EMBL; AY584241; AAS79320.1; -; Genomic_DNA.
DR EMBL; BC063458; AAH63458.1; -; mRNA.
DR RefSeq; NP_005581.2; NM_005590.3.
DR RefSeq; NP_005582.1; NM_005591.3.
DR RefSeq; XP_005274064.1; XM_005274007.1.
DR UniGene; Hs.192649; -.
DR PDB; 3T1I; X-ray; 3.00 A; A/B/C/D=1-411.
DR PDBsum; 3T1I; -.
DR ProteinModelPortal; P49959; -.
DR SMR; P49959; 8-400.
DR DIP; DIP-33238N; -.
DR IntAct; P49959; 16.
DR MINT; MINT-131851; -.
DR STRING; 9606.ENSP00000325863; -.
DR PhosphoSite; P49959; -.
DR DMDM; 17380137; -.
DR PaxDb; P49959; -.
DR PRIDE; P49959; -.
DR DNASU; 4361; -.
DR Ensembl; ENST00000323929; ENSP00000325863; ENSG00000020922.
DR Ensembl; ENST00000323977; ENSP00000326094; ENSG00000020922.
DR GeneID; 4361; -.
DR KEGG; hsa:4361; -.
DR UCSC; uc001peu.2; human.
DR CTD; 4361; -.
DR GeneCards; GC11M094150; -.
DR HGNC; HGNC:7230; MRE11A.
DR HPA; CAB004081; -.
DR HPA; HPA002691; -.
DR MIM; 600814; gene.
DR MIM; 604391; phenotype.
DR neXtProt; NX_P49959; -.
DR Orphanet; 251347; Ataxia-telangiectasia-like disorder.
DR Orphanet; 145; Hereditary breast and ovarian cancer syndrome.
DR PharmGKB; PA30934; -.
DR eggNOG; COG0420; -.
DR HOGENOM; HOG000216581; -.
DR HOVERGEN; HBG052508; -.
DR InParanoid; P49959; -.
DR KO; K10865; -.
DR OrthoDB; EOG7VB2F1; -.
DR PhylomeDB; P49959; -.
DR Reactome; REACT_111183; Meiosis.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_216; DNA Repair.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; MRE11A; human.
DR GeneWiki; MRE11A; -.
DR GenomeRNAi; 4361; -.
DR NextBio; 17163; -.
DR PMAP-CutDB; P49959; -.
DR PRO; PR:P49959; -.
DR ArrayExpress; P49959; -.
DR Bgee; P49959; -.
DR CleanEx; HS_MRE11A; -.
DR Genevestigator; P49959; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030870; C:Mre11 complex; NAS:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0008408; F:3'-5' exonuclease activity; TAS:ProtInc.
DR GO; GO:0003690; F:double-stranded DNA binding; TAS:ProtInc.
DR GO; GO:0030145; F:manganese ion binding; IEA:InterPro.
DR GO; GO:0000014; F:single-stranded DNA endodeoxyribonuclease activity; TAS:ProtInc.
DR GO; GO:0000075; P:cell cycle checkpoint; IEA:Ensembl.
DR GO; GO:0008283; P:cell proliferation; IEA:Ensembl.
DR GO; GO:0032508; P:DNA duplex unwinding; IMP:BHF-UCL.
DR GO; GO:0000724; P:double-strand break repair via homologous recombination; TAS:Reactome.
DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0032876; P:negative regulation of DNA endoreduplication; IMP:BHF-UCL.
DR GO; GO:0033674; P:positive regulation of kinase activity; IDA:BHF-UCL.
DR GO; GO:0031954; P:positive regulation of protein autophosphorylation; IDA:BHF-UCL.
DR GO; GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0007131; P:reciprocal meiotic recombination; TAS:ProtInc.
DR GO; GO:0000019; P:regulation of mitotic recombination; TAS:ProtInc.
DR GO; GO:0007062; P:sister chromatid cohesion; IMP:BHF-UCL.
DR GO; GO:0007129; P:synapsis; IEA:Ensembl.
DR GO; GO:0007004; P:telomere maintenance via telomerase; TAS:ProtInc.
DR InterPro; IPR003701; DNA_repair_Mre11.
DR InterPro; IPR007281; Mre11_DNA-bd.
DR InterPro; IPR004843; PEstase_dom.
DR PANTHER; PTHR10139; PTHR10139; 1.
DR Pfam; PF00149; Metallophos; 1.
DR Pfam; PF04152; Mre11_DNA_bind; 1.
DR PIRSF; PIRSF000882; DSB_repair_MRE11; 1.
DR TIGRFAMs; TIGR00583; mre11; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Ciliopathy;
KW Complete proteome; Disease mutation; DNA damage; DNA repair;
KW Endonuclease; Exonuclease; Hydrolase; Manganese; Meiosis; Nuclease;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 708 Double-strand break repair protein
FT MRE11A.
FT /FTId=PRO_0000138672.
FT ACT_SITE 129 129 Proton donor (By similarity).
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 2 2 Phosphoserine (By similarity).
FT MOD_RES 649 649 Phosphoserine.
FT MOD_RES 688 688 Phosphoserine.
FT MOD_RES 689 689 Phosphoserine.
FT MOD_RES 701 701 Phosphoserine.
FT VAR_SEQ 595 622 Missing (in isoform 2).
FT /FTId=VSP_003262.
FT VARIANT 104 104 S -> C (in cancer).
FT /FTId=VAR_011625.
FT VARIANT 117 117 N -> S (in ATLD).
FT /FTId=VAR_008513.
FT VARIANT 157 157 M -> V (in dbSNP:rs147771140).
FT /FTId=VAR_011626.
FT VARIANT 237 237 F -> C (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036416.
FT VARIANT 302 302 H -> Y (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036417.
FT VARIANT 305 305 R -> W (in ovarian cancer).
FT /FTId=VAR_025528.
FT VARIANT 468 468 D -> G (in dbSNP:rs1805367).
FT /FTId=VAR_019288.
FT VARIANT 503 503 R -> H (in cancer).
FT /FTId=VAR_011627.
FT VARIANT 572 572 R -> Q (in cancer; dbSNP:rs200085146).
FT /FTId=VAR_011628.
FT VARIANT 698 698 M -> V (in dbSNP:rs1805362).
FT /FTId=VAR_019289.
FT CONFLICT 31 31 V -> A (in Ref. 1; AAC78721).
FT HELIX 9 11
FT STRAND 12 18
FT TURN 24 26
FT TURN 30 34
FT HELIX 35 49
FT STRAND 53 57
FT STRAND 62 66
FT HELIX 69 83
FT STRAND 122 124
FT STRAND 128 130
FT TURN 134 137
FT HELIX 140 147
FT STRAND 149 152
FT STRAND 162 164
FT STRAND 167 171
FT STRAND 174 181
FT HELIX 186 194
FT STRAND 198 200
FT HELIX 207 209
FT STRAND 210 216
FT STRAND 223 228
FT HELIX 231 233
FT STRAND 240 243
FT STRAND 250 255
FT TURN 257 259
FT STRAND 262 265
FT HELIX 276 279
FT STRAND 283 290
FT STRAND 293 300
FT STRAND 302 304
FT STRAND 307 313
FT HELIX 314 316
FT TURN 318 320
FT HELIX 328 350
FT TURN 351 353
FT STRAND 355 357
FT STRAND 362 368
FT TURN 370 372
FT HELIX 379 385
FT TURN 386 388
FT STRAND 392 399
SQ SEQUENCE 708 AA; 80593 MW; D94ABFBDDF6106AD CRC64;
MSTADALDDE NTFKILVATD IHLGFMEKDA VRGNDTFVTL DEILRLAQEN EVDFILLGGD
LFHENKPSRK TLHTCLELLR KYCMGDRPVQ FEILSDQSVN FGFSKFPWVN YQDGNLNISI
PVFSIHGNHD DPTGADALCA LDILSCAGFV NHFGRSMSVE KIDISPVLLQ KGSTKIALYG
LGSIPDERLY RMFVNKKVTM LRPKEDENSW FNLFVIHQNR SKHGSTNFIP EQFLDDFIDL
VIWGHEHECK IAPTKNEQQL FYISQPGSSV VTSLSPGEAV KKHVGLLRIK GRKMNMHKIP
LHTVRQFFME DIVLANHPDI FNPDNPKVTQ AIQSFCLEKI EEMLENAERE RLGNSHQPEK
PLVRLRVDYS GGFEPFSVLR FSQKFVDRVA NPKDIIHFFR HREQKEKTGE EINFGKLITK
PSEGTTLRVE DLVKQYFQTA EKNVQLSLLT ERGMGEAVQE FVDKEEKDAI EELVKYQLEK
TQRFLKERHI DALEDKIDEE VRRFRETRQK NTNEEDDEVR EAMTRARALR SQSEESASAF
SADDLMSIDL AEQMANDSDD SISAATNKGR GRGRGRRGGR GQNSASRGGS QRGRADTGLE
TSTRSRNSKT AVSASRNMSI IDAFKSTRQQ PSRNVTTKNY SEVIEVDESD VEEDIFPTTS
KTDQRWSSTS SSKIMSQSQV SKGVDFESSE DDDDDPFMNT SSLRRNRR
//
MIM
600814
*RECORD*
*FIELD* NO
600814
*FIELD* TI
*600814 MEIOTIC RECOMBINATION 11, S. CEREVISIAE, HOMOLOG OF, A; MRE11A
;;MRE11
*FIELD* TX
read more
CLONING
Mutation of the Saccharomyces cerevisiae RAD52 (600392) epistasis group
gene, MRE11, blocks meiotic recombination, confers profound sensitivity
to double-strand break damage, and has a hyperrecombinational phenotype
in mitotic cells. Petrini et al. (1995) isolated a highly conserved
human MRE11 homolog using a 2-hybrid screen for DNA ligase I-interacting
proteins. Human MRE11 shares approximately 50% identity with its yeast
counterpart over the N-terminal half of the protein. MRE11 is expressed
at highest levels in proliferating tissues but is also observed in other
tissues.
GENE FUNCTION
Paull and Gellert (1998) found that MRE11 by itself has 3-prime to
5-prime exonuclease activity that is increased when MRE11 is in a
complex with RAD50 (604040). MRE11 also exhibits endonuclease activity,
as shown by the asymmetric opening of DNA hairpin loops. In conjunction
with a DNA ligase, MRE11 promotes the joining of noncomplementary ends
in vitro by utilizing short homologies near the ends of the DNA
fragments. Sequence identities of 1 to 5 basepairs are present at all of
these junctions, and their diversity is consistent with the products of
nonhomologous end-joining observed in vivo.
Trujillo et al. (1998) isolated a mammalian cell nuclear complex
containing RAD50, MRE11, and nibrin, or p95 (NBS1; 602667), the protein
encoded by the gene mutated in Nijmegen breakage syndrome (NBS; 251260).
The RAD50 complex possessed manganese-dependent single-stranded DNA
endonuclease and 3-prime to 5-prime exonuclease activities. The authors
stated that these nuclease activities are likely to be important for
recombination, repair, and genomic stability.
Carney et al. (1998) demonstrated that p95 is an integral member of the
MRE11/RAD50 complex and that the function of this complex is impaired in
cells from NBS patients.
Zhong et al. (1999) demonstrated association of BRCA1 (113705) with the
RAD50/MRE11/p95 complex. Upon irradiation, BRCA1 was detected in the
nucleus, in discrete foci which colocalized with RAD50. Formation of
irradiation-induced foci positive for BRCA1, RAD50, MRE11, or p95 was
dramatically reduced in HCC/1937 breast cancer cells carrying a
homozygous mutation in BRCA1 but was restored by transfection of
wildtype BRCA1. Ectopic expression of wildtype, but not mutated, BRCA1
in these cells rendered them less sensitive to the DNA damage agent
methyl methanesulfonate. These data suggested to the authors that BRCA1
is important for the cellular responses to DNA damage that are mediated
by the RAD50-MRE11-p95 complex.
Wang et al. (2000) used immunoprecipitation and mass spectrometry
analyses to identify BRCA1-associated proteins. They found that BRCA1 is
part of a large multisubunit protein complex of tumor suppressors, DNA
damage sensors, and signal transducers. They named this complex BASC,
for 'BRCA1-associated genome surveillance complex.' Among the DNA repair
proteins identified in the complex were ATM (607585), BLM (604610), MSH2
(609309), MSH6 (600678), MLH1 (120436), the RAD50-MRE11-NBS1 complex,
and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Confocal
microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1
complex colocalize to large nuclear foci. Wang et al. (2000) suggested
that BASC may serve as a sensor of abnormal DNA structures and/or as a
regulator of the postreplication repair process.
Double-strand DNA breaks (DSBs) pose a major threat to living cells, and
several mechanisms for repairing these lesions have evolved. Eukaryotes
can process DSBs by homologous recombination (HR) on nonhomologous end
joining (NHEJ). NHEJ connects DNA ends irrespective of their sequence,
and it predominates in mitotic cells, particularly during G1 (Takata et
al., 1998). HR requires interaction of the broken DNA molecule with an
intact homologous copy, and allows restoration of the original DNA
sequence. HR is active during G2 of the mitotic cycle and predominates
during meiosis, when the cell creates DSBs, which must be repaired by HR
to ensure proper chromosome segregation. How the cell controls the
choice between the 2 repair pathways was investigated by Goedecke et al.
(1999). They demonstrated a physical interaction between the mammalian
Ku70 (152690), which is essential for NHEJ (Baumann and West, 1998), and
MRE11, which functions both in NHEJ and meiotic HR. Moreover, they
showed that irradiated cells deficient for Ku70 are incapable of
targeting Mre11 to subnuclear foci that may represent DNA-repair
complexes. Nevertheless, Ku70 and Mre11 were differentially expressed
during meiosis. In the mouse testis, Mre11 and Ku70 colocalized in
nuclei of somatic cells and in the XY bivalent. In early meiotic
prophase, however, when meiotic recombination is most probably
initiated, Mre11 was abundant, whereas Ku70 was not detectable. Goedecke
et al. (1999) proposed that Ku70 acts as a switch between the 2 DSB
repair pathways. When present, Ku70 destines DSBs for NHEJ by binding to
DNA ends and attracting other factors for NHEJ, including Mre11; when
absent, it allows participation of DNA ends and Mre11 in the meiotic HR
pathway.
Zhu et al. (2000) showed by coimmunoprecipitation studies that a small
fraction of RAD50, MRE11, and p95 is associated with the telomeric
repeat-binding factor TRF2 (602027). Indirect immunofluorescence
demonstrated the presence of RAD50 and MRE11 at interphase telomeres.
Although the MRE11 complex accumulated in irradiation-induced foci
(IRIFs) in response to gamma-irradiation, TRF2 did not relocate to IRIFs
and irradiation did not affect the association of TRF2 with the MRE11
complex, arguing against a role for TRF2 in double-strand break repair.
Zhu et al. (2000) proposed that the MRE11 complex functions at
telomeres, possibly by modulating t-loop formation.
Costanzo et al. (2001) cloned Xenopus Mre11 and studied its role in DNA
replication and DNA damage checkpoint in cell-free extracts. DSBs
stimulated the phosphorylation and 3-prime-to-5-prime exonuclease
activity of the Mre11 complex. This induced phosphorylation was ATM
independent. Phosphorylated Mre11 was found associated with replicating
nuclei. The Mre11 complex was required to yield normal DNA replication
products. Genomic DNA replicated in extracts immunodepleted of Mre11
complex accumulated DSBs, as demonstrated by TUNEL assay and reactivity
to phosphorylated histone H2AX (601772) antibodies. In contrast, the
ATM-dependent DNA damage checkpoint that blocks DNA replication
initiation was Mre11 independent. These results suggested that the
function of the Xenopus Mre11 complex is to repair DSBs that arise
during normal DNA replication, thus unraveling a critical link between
recombination-dependent repair and DNA replication.
Falck et al. (2002) demonstrated that experimental blockade of either
the NBS1-MRE11 function or the CHK2 (604373)-triggered events leads to a
partial radioresistant DNA synthesis phenotype in human cells. In
contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A
(116947)-CDK2 (116953) pathways entirely abolishes inhibition of DNA
synthesis induced by ionizing radiation, resulting in complete
radioresistant DNA synthesis analogous to that caused by defective ATM.
In addition, CDK2-dependent loading of CDC45 (603465) onto replication
origins, a prerequisite for recruitment of DNA polymerase, was prevented
upon irradiation of normal or NBS1/MRE11-defective cells but not cells
with defective ATM. Falck et al. (2002) concluded that in response to
ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2
parallel branches of the DNA damage-dependent S-phase checkpoint that
cooperate by inhibiting distinct steps of DNA replication.
In mammalian cells, a conserved multiprotein complex of MRE11, RAD50,
and NBS1 (MRN) is important for double-strand break repair, meiotic
recombination, and telomere maintenance. In the absence of the early
region E4, the double-stranded genome of adenoviruses is joined into
concatemers too large to be packaged. Stracker et al. (2002)
investigated the cellular proteins involved in the concatemer formation
and how they are inactivated by E4 products during a wildtype infection.
They demonstrated that concatemerization requires functional MRE11 and
NBS1, and that these proteins are found at foci adjacent to viral
replication centers. Infection with wildtype virus results in both
reorganization and degradation of members of the MRN complex. These
activities are mediated by 3 viral oncoproteins that prevent
concatemerization. This targeting of cellular proteins involved in the
genomic stability suggested a mechanism for 'hit-and-run' transformation
observed for these viral oncoproteins.
Franchitto and Pichierri (2002) reviewed the roles of RECQL2 (604611)
and RECQL3 (604610) in resolution of a stall in DNA replication, as well
as their possible interaction with the MRN complex.
Boisvert et al. (2005) found that PRMT1 (HRMT1L2; 602950) arginine
methylated MRE11 in HeLa cells. Mutation of the arginines within the GAR
domain of MRE11 severely impaired the exonuclease activity of MRE11 but
did not influence its ability to form a complex with RAD50 and NBS1.
Inhibition of MRE11 methylation resulted in S-phase checkpoint defects,
which were rescued by the MRE11-RAD50-NBS1 complex. Boisvert et al.
(2005) concluded that arginine methylation regulates the activity of the
MRE11-RAD50-NBS1 complex during the intra-S-phase DNA damage checkpoint
response.
Larson et al. (2005) found that MRE11 associated specifically with
rearranged Ig genes in hypermutating B cells, whereas APE1 (APEX;
107748), the major apurinic/apyrimidinic (AP) endonuclease in faithful
base excision repair, did not. Purified recombinant MRE11/RAD50 cleaved
DNA at AP sites within single-stranded regions of DNA, suggesting that
at transcribed Ig genes, cleavage may be coordinated with deamination by
AID (AICDA; 605257) and deglycosylation by UNG2 (607752) to produce the
single-stranded breaks that undergo subsequent mutagenic repair and
recombination.
Zhong et al. (2005) tested whether the MRN complex has a global
controlling role over ATR (601215) through the study of MRN deficiencies
generated by RNA interference. The MRN complex was required for
ATR-dependent phosphorylation of SMC1A (300040), which acts within
chromatin to ensure sister chromatid cohesion and to effect several DNA
damage responses. Novel phenotypes caused by MRN deficiency that support
a functional link between this complex, ATR, and SMC1A, included
hypersensitivity to UV exposure, a defective UV responsive intra-S phase
checkpoint, and a specific pattern of genomic instability. Zhong et al.
(2005) concluded that there is a controlling role for the MRN complex
over the ATR kinase, and that downstream events under this control are
broad, including both chromatin-associated and diffuse signaling
factors.
Deng et al. (2009) addressed the question of whether the mammalian MRN
complex promotes repair at dysfunctional telomeres, by using mouse
alleles that either inactivated the entire MRN complex or eliminated
only the nuclease activities of MRE11. Deng et al. (2009) found that
cells lacking MRN did not activate ATM when telomeric repeat binding
factor-2 (TRF2; 602027) was removed from telomeres, and ligase-4 (LIG4;
601837)-dependent chromosome end-to-end fusions were markedly reduced.
Residual chromatid fusions involve only telomeres generated by leading
strand synthesis. Notably, although cells deficient for MRE11 nuclease
activity efficiently activated ATM and recruited 53BP1 (605230) to
deprotected telomeres, the 3-prime telomeric overhang persisted to
prevent nonhomologous end joining (NHEJ)-mediated chromosomal fusions.
Removal of shelterin proteins that protect the 3-prime overhang in the
setting of MRE11 nuclease deficiency restored LIG4-dependent chromosome
fusions. Deng et al. (2009) concluded that their data indicated a
critical role for the MRN complex in sensing dysfunctional telomeres,
and showed that in the absence of TRF2, MRE11 nuclease activity removes
the 3-prime telomeric overhang to promote chromosome fusions. MRE11 can
also protect newly replicated leading strand telomeres from NHEJ by
promoting 5-prime strand resection to generate POT1a (see 606478)-TPP1
(607998)-bound 3-prime overhangs.
Garcia et al. (2011) used Saccharomyces cerevisiae to reveal a role for
the Mre11 exonuclease during the resection of Spo11 (605114)-linked
5-prime DNA termini in vivo. They showed that the residual resection
observed in Exo1 (606063)-mutant cells is dependent on Mre11, and that
both exonuclease activities are required for efficient double-strand
break repair. Previous work had indicated that resection traverses
unidirectionally. Using a combination of physical assays for 5-prime-end
processing, Garcia et al. (2011) observed results indicating an
alternative mechanism involving bidirectional resection. First, Mre11
nicks the strand to be resected up to 300 nucleotides from the 5-prime
terminus of the double-strand break, much further away than previously
assumed. Second, this nick enables resection in a bidirectional manner,
using Exo1 in the 5-prime-to-3-prime direction away from the
double-strand break, and Mre11 in the 3-prime-to-5-prime direction
towards the double-strand break end. Mre11 exonuclease activity also
confers resistance to DNA damage in cycling cells, suggesting that
Mre11-catalyzed resection may be a general feature of various DNA repair
pathways.
BIOCHEMICAL FEATURES
To clarify functions of the MRE11/RAD50 complex in DNA double-strand
break repair, Hopfner et al. (2001) reported P. furiosus Mre11 crystal
structures, which revealed a protein phosphatase-like
dimanganese-binding domain capped by a unique domain that controls
active site access. These structures unify the multiple nuclease
activities of Mre11 in a single endo/exonuclease mechanism. Mapping
human and yeast MRE11 mutations revealed eukaryotic macromolecular
interaction sites. Furthermore, the structure of the P. furiosus Rad50
ABC-ATPase with its adjacent coiled-coil defines a compact
Mre11/Rad50-ATPase complex and suggests that RAD50-ATP-driven
conformational switching directly controls the MRE11 exonuclease.
Electron microscopy, small-angle x-ray scattering, and
ultracentrifugation data of human and P. furiosus MRE11/RAD50 complex
revealed a dual functional complex consisting of a (MRE11)2/(RAD50)2
heterotetrameric DNA-processing head and a double coiled-coil linker.
The human RAD50/MRE11/NBS1 complex (R/M/N) has a dynamic molecular
architecture consisting of a globular DNA binding domain from which two
50-nanometer coiled coils protrude. The coiled coils are flexible and
their apices can self-associate. The flexibility of the coiled coils
allows their apices to adopt an orientation favorable for interaction.
However, this also allows interaction between the tips of the 2 coiled
coils within the same complex, which competes with and frustrates the
intercomplex interaction required for DNA tethering. Moreno-Herrero et
al. (2005) showed that the dynamic architecture of the R/M/N complex is
markedly affected by DNA binding. DNA binding by the R/M/N globular
domain leads to parallel orientation of the coiled coils; this prevents
intracomplex interactions and favors intercomplex associations needed
for DNA tethering. The R/M/N complex thus is an example of a biologic
nanomachine in which binding to its ligand, in this case DNA, affects
the functional conformation of a domain located 50 nanometers distant.
MAPPING
By analysis of somatic cell hybrids and by fluorescence in situ
hybridization, Petrini et al. (1995) mapped the MRE11 gene to 11q21. An
MRE11-related locus was found on 7q11.2-q11.3.
MOLECULAR GENETICS
In 2 families with ataxia-telangiectasia-like disorder (ATLD; 604391),
Stewart et al. (1999) identified mutations in the MRE11A gene.
Consistent with the clinical outcome of these mutations, cells
established from the affected individuals within the 2 families
exhibited many of the features characteristic of both
ataxia-telangiectasia (208900) and NBS, including chromosomal
instability, increased sensitivity to ionizing radiation, defective
induction of stress-activated signal transduction pathways, and
radioresistant DNA synthesis. These data strengthened the molecular
connection between double-stranded break recognition by the MRE11A/RAD50
(604040)/NBS1 (602667) protein complex and the ability of the cell to
activate the DNA damage-response pathway controlled by ATM (607585).
Delia et al. (2004) described 2 sibs with late-onset cerebellar
degeneration, absence of telangiectasia, and absence of malignancy
through their fourth decade. Both patients were compound heterozygotes
for MRE11 mutations (600814.0003 and 600814.0004). Lymphoblastoid cell
lines (LCLs) derived from these sibs exhibited normal ATM expression,
but were defective for MRE11, RAD50, and NBS1 protein expression.
Response to gamma-radiation was abnormal, as evident by the enhanced
radiosensitivity, attenuated autophosphorylation of serine-1981 on ATM
and phosphorylation of serine-15 on p53 (191170) and serine-966 on
SMC1A, failure to form Mre11 nuclear foci, and defective G1 checkpoint
arrest. Fibroblasts from the 2 sibs, but not LCLs, showed impaired
ATM-dependent Chk2 (CHEK2; 604373) phosphorylation.
Fernet et al. (2005) described 10 patients from 3 unrelated Saudi
Arabian families with ATLD. All patients were homozygous for a W210C
mutation (600814.0005) in the MRE11A gene. In fibroblast cultures
established from 2 individuals, there were high constitutive levels of
MRE11A and RAD50 proteins compared with controls but a very low level of
the NBS1 protein. After exposure to ionizing radiation, a dose-dependent
defect in ATM serine-1981, p53 serine-15 and Chek2 phosphorylation, and
p53 stabilization were noted, together with a failure to form MRE11A
foci and enhanced radiation sensitivity. Fernet et al. (2005)
hypothesized that the MRE11A/RAD50/NBS1 complex may act as a sensor of
DNA double-strand breaks, acting upstream of ATM.
*FIELD* AV
.0001
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, ARG633TER
In 2 first cousins with ataxia-telangiectasia-like disorder (ATLD;
604391) from a large inbred family from Pakistan originally reported by
Hernandez et al. (1993), Stewart et al. (1999) identified a homozygous
C-to-T transition at nucleotide 1897 of the MRE11A gene, resulting in an
arg633-to-ter (R633X) mutation. Both patients had progressive cerebellar
degeneration, but neither patient showed any intellectual impairment.
Chaki et al. (2012) identified a homozygous R633X mutation in 2 sibs,
born of consanguineous Pakistani parents, with ataxia and cerebellar
vermis hypoplasia. One patient had dysarthria and myoclonus. Although
the patients were part of a larger group of patients with
nephronophthisis (see, e.g., NPHP1, 256100) and related ciliopathies,
neither had renal failure or retinal involvement. The mutation was found
by homozygosity mapping and whole-exome sequencing. The report linked
the pathogenesis of NPHP and ciliopathy to defects in DNA damage
response signaling.
.0002
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, ASN117SER
In 2 brothers with ataxia-telangiectasia-like disorder (604391)
originally reported by Klein et al. (1996), Stewart et al. (1999)
identified a heterozygous A-to-G transition at nucleotide 350 of the
MRE11A gene, resulting in an asn117-to-ser (N117S) substitution on the
paternal allele. No maternally derived mutation was detected by DNA
sequencing, suggesting that the mother was heterozygous for a null
MRE11A mutation. Western blotting showed reduced MRE11A levels in
maternally-derived cells. The boys had early-childhood onset of
progressive cerebellar degeneration causing cerebellar ataxia and
oculomotor apraxia, but no telangiectasia. Pitts et al. (2001) later
identified a heterozygous truncating mutation in the MRE11A gene
(600814.0003) on the maternal allele. The findings confirmed autosomal
recessive inheritance of the disorder.
.0003
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, ARG571TER
In affected members of the family with ataxia-telangiectasia-like
disorder (604391) originally reported by Klein et al. (1996), in whom
Stewart et al. (1999) had identified a heterozygous missense mutation in
the MRE11A gene (600814.0002) on the paternal allele, Pitts et al.
(2001) identified a heterozygous 1714C-T transition in exon 15 of the
MRE11A gene, resulting in an arg571-to-ter (R571X) substitution on the
maternal allele. This maternally inherited mutant allele had not been
detected previously because transcripts derived from it underwent
nonsense-mediated mRNA decay.
.0004
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, THR481LYS
Delia et al. (2004) described 2 Italian sibs with late-onset cerebellar
degeneration that progressed slowly until puberty, absence of
telangiectasia, and absence of malignancy through their fourth decade
(604391). In both sibs, the authors identified compound heterozygosity
for the R571X mutation (600814.0003) and a 1422C-A transversion in exon
15 of the MRE11A gene, resulting in a thr481-to-lys (T481K)
substitution. The T481K mutation was maternally inherited, and the
paternal R571X allele was null as a result of NMD.
.0005
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, TRP210CYS
In 10 patients from 3 unrelated Saudi Arabian families with ATLD
(604391), Fernet et al. (2005) identified homozygosity for a 630G-C
transversion in exon 7 of the MRE11A gene, resulting in a trp210-to-cys
(W210C) substitution between motifs III and IV of the N-terminal
nuclease domain. Patients presented with an early-onset, slowly
progressive, ataxia plus ocular apraxia phenotype with an absence of
tumor development, even in the oldest 37-year-old patient.
Extraneurologic features, such as telangiectasia, raised
alpha-fetoprotein, and reduced immunoglobulin levels, were absent.
*FIELD* RF
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11. Garcia, V.; Phelps, S. E. L.; Gray, S.; Neale, M. J.: Bidirectional
resection of DNA double-strand breaks by Mre11 and Exo1. Nature 479:
241-244, 2011.
12. Goedecke, W.; Eijpe, M.; Offenberg, H. H.; van Aalderen, M.; Heyting,
C.: Mre11 and Ku70 interact in somatic cells, but are differentially
expressed in early meiosis. Nature Genet. 23: 194-198, 1999.
13. Hernandez, D.; McConville, C. M.; Stacey, M.; Woods, C. G.; Brown,
M. M.; Shutt, P.; Rysiecki, G.; Taylor, A. M. R.: A family showing
no evidence of linkage between the ataxia telangiectasia gene and
chromosome 1q22-23. J. Med. Genet. 30: 135-140, 1993.
14. Hopfner, K.-P.; Karcher, A.; Craig, L.; Woo, T. T.; Carney, J.
P.; Tainer, J. A.: Structural biochemistry and interaction architecture
of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase. Cell 105:
473-485, 2001.
15. Klein, C.; Wenning, G. K.; Quinn, N. P.; Marsden, C. D.: Ataxia
without telangiectasia masquerading as benign hereditary chorea. Mov.
Disord. 11: 217-220, 1996.
16. Larson, E. D.; Cummings, W. J.; Bednarski, D. W.; Maizels, N.
: MRE11/RAD50 cleaves DNA in the AID/UNG-dependent pathway of immunoglobulin
gene diversification. Molec. Cell 20: 367-375, 2005.
17. Moreno-Herrero, F.; de Jager, M.; Dekker, N. H.; Kanaar, R.; Wyman,
C.; Dekker, C.: Mesoscale conformational changes in the DNA-repair
complex Rad50/Mre11/Nbs1 upon binding DNA. Nature 437: 440-443,
2005.
18. Paull, T. T.; Gellert, M.: The 3-prime to 5-prime exonuclease
activity of Mre11 facilitates repair of DNA double-strand breaks. Molec.
Cell 1: 969-979, 1998.
19. Petrini, J. H. J.; Walsh, M. E.; DiMare, C.; Chen, X.-N.; Korenberg,
J. R.; Weaver, D. T.: Isolation and characterization of the human
MRE11 homologue. Genomics 29: 80-86, 1995.
20. Pitts, S. A.; Kullar, H. S.; Stankovic, T.; Stewart, G. S.; Last,
J. I. K.; Bedenham, T.; Armstrong, S. J.; Piane, M.; Chessa, L.; Taylor,
A. M. R.; Byrd, P. J.: hMRE11: genomic structure and a null mutation
identified in a transcript protected from nonsense-mediated mRNA decay. Hum.
Molec. Genet. 10: 1155-1162, 2001.
21. Stewart, G. S.; Maser, R. S.; Stankovic, T.; Bressan, D. A.; Kaplan,
M. I.; Jaspers, N. G. J.; Raams, A.; Byrd, P. J.; Petrini, J. H. J.;
Taylor, A. M. R.: The DNA double-strand break repair gene hMRE11
is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99:
577-587, 1999.
22. Stracker, T. H.; Carson, C. T.; Weitzman, M. D.: Adenovirus oncoproteins
inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature 418:
348-352, 2002.
23. Takata, M.; Sasaki, M. S.; Sonoda, E.; Morrison, C.; Hashimoto,
M.; Utsumi, H.; Yamaguchi-Iwai, Y.; Shinohara, A.; Takeda, S.: Homologous
recombination and non-homologous end-joining pathways of DNA double-strand
break repair have overlapping roles in the maintenance of chromosomal
integrity in vertebrate cells. EMBO J. 17: 5497-5508, 1998.
24. Trujillo, K. M.; Yuan, S.-S. F.; Lee, E. Y.-H. P.; Sung, P.:
Nuclease activities in a complex of human recombination and DNA repair
factors Rad50, Mre11, and p95. J. Biol. Chem. 273: 21447-21450,
1998.
25. Wang, Y.; Cortez, D.; Yazdi, P.; Neff, N.; Elledge, S. J.; Qin,
J.: BASC, a super complex of BRCA1-associated proteins involved in
the recognition and repair of aberrant DNA structures. Genes Dev. 14:
927-939, 2000.
26. Zhong, H.; Bryson, A.; Eckersdorff, M.; Ferguson, D. O.: Rad50
depletion impacts upon ATR-dependent DNA damage responses. Hum. Molec.
Genet. 14: 2685-2693, 2005.
27. Zhong, Q.; Chen, C.-F.; Li, S.; Chen, Y.; Wang, C.-C.; Xiao, J.;
Chen, P.-L.; Sharp, Z. D.; Lee, W.-H.: Association of BRCA1 with
the hRad50-hMre11-p95 complex and the DNA damage response. Science 285:
747-750, 1999.
28. Zhu, X.-D.; Kuster, B.; Mann, M.; Petrini, J. H. J.; de Lange,
T.: Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2
and human telomeres. Nature Genet. 25: 347-352, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 10/4/2012
Ada Hamosh - updated: 12/21/2011
Ada Hamosh - updated: 9/4/2009
George E. Tiller - updated: 12/10/2008
George E. Tiller - updated: 11/8/2007
George E. Tiller - updated: 3/21/2007
Paul J. Converse - updated: 2/9/2006
Ada Hamosh - updated: 11/3/2005
Patricia A. Hartz - updated: 4/19/2005
George E. Tiller - updated: 12/4/2003
Ada Hamosh - updated: 7/24/2002
Ada Hamosh - updated: 3/28/2002
Stylianos E. Antonarakis - updated: 8/3/2001
Stylianos E. Antonarakis - updated: 6/4/2001
Paul J. Converse - updated: 11/16/2000
Victor A. McKusick - updated: 6/27/2000
Stylianos E. Antonarakis - updated: 12/29/1999
Victor A. McKusick - updated: 9/28/1999
Ada Hamosh - updated: 7/30/1999
Rebekah S. Rasooly - updated: 7/22/1999
Stylianos E. Antonarakis - updated: 8/3/1998
*FIELD* CD
Victor A. McKusick: 10/2/1995
*FIELD* ED
carol: 10/08/2012
terry: 10/5/2012
ckniffin: 10/4/2012
alopez: 1/5/2012
terry: 12/21/2011
alopez: 9/8/2009
terry: 9/4/2009
wwang: 12/10/2008
wwang: 12/3/2007
terry: 11/8/2007
wwang: 3/26/2007
terry: 3/21/2007
mgross: 2/9/2006
alopez: 11/7/2005
terry: 11/3/2005
mgross: 4/21/2005
terry: 4/19/2005
mgross: 4/14/2005
mgross: 12/4/2003
ckniffin: 3/11/2003
alopez: 11/14/2002
cwells: 7/26/2002
terry: 7/24/2002
carol: 3/29/2002
cwells: 3/29/2002
terry: 3/28/2002
cwells: 10/30/2001
cwells: 10/16/2001
mgross: 8/3/2001
mgross: 6/4/2001
joanna: 1/17/2001
mgross: 11/16/2000
alopez: 6/27/2000
mgross: 1/3/2000
mgross: 12/29/1999
terry: 12/1/1999
alopez: 9/30/1999
terry: 9/28/1999
alopez: 7/30/1999
mgross: 7/22/1999
carol: 8/20/1998
carol: 8/4/1998
terry: 8/3/1998
mark: 10/2/1995
*RECORD*
*FIELD* NO
600814
*FIELD* TI
*600814 MEIOTIC RECOMBINATION 11, S. CEREVISIAE, HOMOLOG OF, A; MRE11A
;;MRE11
*FIELD* TX
read more
CLONING
Mutation of the Saccharomyces cerevisiae RAD52 (600392) epistasis group
gene, MRE11, blocks meiotic recombination, confers profound sensitivity
to double-strand break damage, and has a hyperrecombinational phenotype
in mitotic cells. Petrini et al. (1995) isolated a highly conserved
human MRE11 homolog using a 2-hybrid screen for DNA ligase I-interacting
proteins. Human MRE11 shares approximately 50% identity with its yeast
counterpart over the N-terminal half of the protein. MRE11 is expressed
at highest levels in proliferating tissues but is also observed in other
tissues.
GENE FUNCTION
Paull and Gellert (1998) found that MRE11 by itself has 3-prime to
5-prime exonuclease activity that is increased when MRE11 is in a
complex with RAD50 (604040). MRE11 also exhibits endonuclease activity,
as shown by the asymmetric opening of DNA hairpin loops. In conjunction
with a DNA ligase, MRE11 promotes the joining of noncomplementary ends
in vitro by utilizing short homologies near the ends of the DNA
fragments. Sequence identities of 1 to 5 basepairs are present at all of
these junctions, and their diversity is consistent with the products of
nonhomologous end-joining observed in vivo.
Trujillo et al. (1998) isolated a mammalian cell nuclear complex
containing RAD50, MRE11, and nibrin, or p95 (NBS1; 602667), the protein
encoded by the gene mutated in Nijmegen breakage syndrome (NBS; 251260).
The RAD50 complex possessed manganese-dependent single-stranded DNA
endonuclease and 3-prime to 5-prime exonuclease activities. The authors
stated that these nuclease activities are likely to be important for
recombination, repair, and genomic stability.
Carney et al. (1998) demonstrated that p95 is an integral member of the
MRE11/RAD50 complex and that the function of this complex is impaired in
cells from NBS patients.
Zhong et al. (1999) demonstrated association of BRCA1 (113705) with the
RAD50/MRE11/p95 complex. Upon irradiation, BRCA1 was detected in the
nucleus, in discrete foci which colocalized with RAD50. Formation of
irradiation-induced foci positive for BRCA1, RAD50, MRE11, or p95 was
dramatically reduced in HCC/1937 breast cancer cells carrying a
homozygous mutation in BRCA1 but was restored by transfection of
wildtype BRCA1. Ectopic expression of wildtype, but not mutated, BRCA1
in these cells rendered them less sensitive to the DNA damage agent
methyl methanesulfonate. These data suggested to the authors that BRCA1
is important for the cellular responses to DNA damage that are mediated
by the RAD50-MRE11-p95 complex.
Wang et al. (2000) used immunoprecipitation and mass spectrometry
analyses to identify BRCA1-associated proteins. They found that BRCA1 is
part of a large multisubunit protein complex of tumor suppressors, DNA
damage sensors, and signal transducers. They named this complex BASC,
for 'BRCA1-associated genome surveillance complex.' Among the DNA repair
proteins identified in the complex were ATM (607585), BLM (604610), MSH2
(609309), MSH6 (600678), MLH1 (120436), the RAD50-MRE11-NBS1 complex,
and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Confocal
microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1
complex colocalize to large nuclear foci. Wang et al. (2000) suggested
that BASC may serve as a sensor of abnormal DNA structures and/or as a
regulator of the postreplication repair process.
Double-strand DNA breaks (DSBs) pose a major threat to living cells, and
several mechanisms for repairing these lesions have evolved. Eukaryotes
can process DSBs by homologous recombination (HR) on nonhomologous end
joining (NHEJ). NHEJ connects DNA ends irrespective of their sequence,
and it predominates in mitotic cells, particularly during G1 (Takata et
al., 1998). HR requires interaction of the broken DNA molecule with an
intact homologous copy, and allows restoration of the original DNA
sequence. HR is active during G2 of the mitotic cycle and predominates
during meiosis, when the cell creates DSBs, which must be repaired by HR
to ensure proper chromosome segregation. How the cell controls the
choice between the 2 repair pathways was investigated by Goedecke et al.
(1999). They demonstrated a physical interaction between the mammalian
Ku70 (152690), which is essential for NHEJ (Baumann and West, 1998), and
MRE11, which functions both in NHEJ and meiotic HR. Moreover, they
showed that irradiated cells deficient for Ku70 are incapable of
targeting Mre11 to subnuclear foci that may represent DNA-repair
complexes. Nevertheless, Ku70 and Mre11 were differentially expressed
during meiosis. In the mouse testis, Mre11 and Ku70 colocalized in
nuclei of somatic cells and in the XY bivalent. In early meiotic
prophase, however, when meiotic recombination is most probably
initiated, Mre11 was abundant, whereas Ku70 was not detectable. Goedecke
et al. (1999) proposed that Ku70 acts as a switch between the 2 DSB
repair pathways. When present, Ku70 destines DSBs for NHEJ by binding to
DNA ends and attracting other factors for NHEJ, including Mre11; when
absent, it allows participation of DNA ends and Mre11 in the meiotic HR
pathway.
Zhu et al. (2000) showed by coimmunoprecipitation studies that a small
fraction of RAD50, MRE11, and p95 is associated with the telomeric
repeat-binding factor TRF2 (602027). Indirect immunofluorescence
demonstrated the presence of RAD50 and MRE11 at interphase telomeres.
Although the MRE11 complex accumulated in irradiation-induced foci
(IRIFs) in response to gamma-irradiation, TRF2 did not relocate to IRIFs
and irradiation did not affect the association of TRF2 with the MRE11
complex, arguing against a role for TRF2 in double-strand break repair.
Zhu et al. (2000) proposed that the MRE11 complex functions at
telomeres, possibly by modulating t-loop formation.
Costanzo et al. (2001) cloned Xenopus Mre11 and studied its role in DNA
replication and DNA damage checkpoint in cell-free extracts. DSBs
stimulated the phosphorylation and 3-prime-to-5-prime exonuclease
activity of the Mre11 complex. This induced phosphorylation was ATM
independent. Phosphorylated Mre11 was found associated with replicating
nuclei. The Mre11 complex was required to yield normal DNA replication
products. Genomic DNA replicated in extracts immunodepleted of Mre11
complex accumulated DSBs, as demonstrated by TUNEL assay and reactivity
to phosphorylated histone H2AX (601772) antibodies. In contrast, the
ATM-dependent DNA damage checkpoint that blocks DNA replication
initiation was Mre11 independent. These results suggested that the
function of the Xenopus Mre11 complex is to repair DSBs that arise
during normal DNA replication, thus unraveling a critical link between
recombination-dependent repair and DNA replication.
Falck et al. (2002) demonstrated that experimental blockade of either
the NBS1-MRE11 function or the CHK2 (604373)-triggered events leads to a
partial radioresistant DNA synthesis phenotype in human cells. In
contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A
(116947)-CDK2 (116953) pathways entirely abolishes inhibition of DNA
synthesis induced by ionizing radiation, resulting in complete
radioresistant DNA synthesis analogous to that caused by defective ATM.
In addition, CDK2-dependent loading of CDC45 (603465) onto replication
origins, a prerequisite for recruitment of DNA polymerase, was prevented
upon irradiation of normal or NBS1/MRE11-defective cells but not cells
with defective ATM. Falck et al. (2002) concluded that in response to
ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2
parallel branches of the DNA damage-dependent S-phase checkpoint that
cooperate by inhibiting distinct steps of DNA replication.
In mammalian cells, a conserved multiprotein complex of MRE11, RAD50,
and NBS1 (MRN) is important for double-strand break repair, meiotic
recombination, and telomere maintenance. In the absence of the early
region E4, the double-stranded genome of adenoviruses is joined into
concatemers too large to be packaged. Stracker et al. (2002)
investigated the cellular proteins involved in the concatemer formation
and how they are inactivated by E4 products during a wildtype infection.
They demonstrated that concatemerization requires functional MRE11 and
NBS1, and that these proteins are found at foci adjacent to viral
replication centers. Infection with wildtype virus results in both
reorganization and degradation of members of the MRN complex. These
activities are mediated by 3 viral oncoproteins that prevent
concatemerization. This targeting of cellular proteins involved in the
genomic stability suggested a mechanism for 'hit-and-run' transformation
observed for these viral oncoproteins.
Franchitto and Pichierri (2002) reviewed the roles of RECQL2 (604611)
and RECQL3 (604610) in resolution of a stall in DNA replication, as well
as their possible interaction with the MRN complex.
Boisvert et al. (2005) found that PRMT1 (HRMT1L2; 602950) arginine
methylated MRE11 in HeLa cells. Mutation of the arginines within the GAR
domain of MRE11 severely impaired the exonuclease activity of MRE11 but
did not influence its ability to form a complex with RAD50 and NBS1.
Inhibition of MRE11 methylation resulted in S-phase checkpoint defects,
which were rescued by the MRE11-RAD50-NBS1 complex. Boisvert et al.
(2005) concluded that arginine methylation regulates the activity of the
MRE11-RAD50-NBS1 complex during the intra-S-phase DNA damage checkpoint
response.
Larson et al. (2005) found that MRE11 associated specifically with
rearranged Ig genes in hypermutating B cells, whereas APE1 (APEX;
107748), the major apurinic/apyrimidinic (AP) endonuclease in faithful
base excision repair, did not. Purified recombinant MRE11/RAD50 cleaved
DNA at AP sites within single-stranded regions of DNA, suggesting that
at transcribed Ig genes, cleavage may be coordinated with deamination by
AID (AICDA; 605257) and deglycosylation by UNG2 (607752) to produce the
single-stranded breaks that undergo subsequent mutagenic repair and
recombination.
Zhong et al. (2005) tested whether the MRN complex has a global
controlling role over ATR (601215) through the study of MRN deficiencies
generated by RNA interference. The MRN complex was required for
ATR-dependent phosphorylation of SMC1A (300040), which acts within
chromatin to ensure sister chromatid cohesion and to effect several DNA
damage responses. Novel phenotypes caused by MRN deficiency that support
a functional link between this complex, ATR, and SMC1A, included
hypersensitivity to UV exposure, a defective UV responsive intra-S phase
checkpoint, and a specific pattern of genomic instability. Zhong et al.
(2005) concluded that there is a controlling role for the MRN complex
over the ATR kinase, and that downstream events under this control are
broad, including both chromatin-associated and diffuse signaling
factors.
Deng et al. (2009) addressed the question of whether the mammalian MRN
complex promotes repair at dysfunctional telomeres, by using mouse
alleles that either inactivated the entire MRN complex or eliminated
only the nuclease activities of MRE11. Deng et al. (2009) found that
cells lacking MRN did not activate ATM when telomeric repeat binding
factor-2 (TRF2; 602027) was removed from telomeres, and ligase-4 (LIG4;
601837)-dependent chromosome end-to-end fusions were markedly reduced.
Residual chromatid fusions involve only telomeres generated by leading
strand synthesis. Notably, although cells deficient for MRE11 nuclease
activity efficiently activated ATM and recruited 53BP1 (605230) to
deprotected telomeres, the 3-prime telomeric overhang persisted to
prevent nonhomologous end joining (NHEJ)-mediated chromosomal fusions.
Removal of shelterin proteins that protect the 3-prime overhang in the
setting of MRE11 nuclease deficiency restored LIG4-dependent chromosome
fusions. Deng et al. (2009) concluded that their data indicated a
critical role for the MRN complex in sensing dysfunctional telomeres,
and showed that in the absence of TRF2, MRE11 nuclease activity removes
the 3-prime telomeric overhang to promote chromosome fusions. MRE11 can
also protect newly replicated leading strand telomeres from NHEJ by
promoting 5-prime strand resection to generate POT1a (see 606478)-TPP1
(607998)-bound 3-prime overhangs.
Garcia et al. (2011) used Saccharomyces cerevisiae to reveal a role for
the Mre11 exonuclease during the resection of Spo11 (605114)-linked
5-prime DNA termini in vivo. They showed that the residual resection
observed in Exo1 (606063)-mutant cells is dependent on Mre11, and that
both exonuclease activities are required for efficient double-strand
break repair. Previous work had indicated that resection traverses
unidirectionally. Using a combination of physical assays for 5-prime-end
processing, Garcia et al. (2011) observed results indicating an
alternative mechanism involving bidirectional resection. First, Mre11
nicks the strand to be resected up to 300 nucleotides from the 5-prime
terminus of the double-strand break, much further away than previously
assumed. Second, this nick enables resection in a bidirectional manner,
using Exo1 in the 5-prime-to-3-prime direction away from the
double-strand break, and Mre11 in the 3-prime-to-5-prime direction
towards the double-strand break end. Mre11 exonuclease activity also
confers resistance to DNA damage in cycling cells, suggesting that
Mre11-catalyzed resection may be a general feature of various DNA repair
pathways.
BIOCHEMICAL FEATURES
To clarify functions of the MRE11/RAD50 complex in DNA double-strand
break repair, Hopfner et al. (2001) reported P. furiosus Mre11 crystal
structures, which revealed a protein phosphatase-like
dimanganese-binding domain capped by a unique domain that controls
active site access. These structures unify the multiple nuclease
activities of Mre11 in a single endo/exonuclease mechanism. Mapping
human and yeast MRE11 mutations revealed eukaryotic macromolecular
interaction sites. Furthermore, the structure of the P. furiosus Rad50
ABC-ATPase with its adjacent coiled-coil defines a compact
Mre11/Rad50-ATPase complex and suggests that RAD50-ATP-driven
conformational switching directly controls the MRE11 exonuclease.
Electron microscopy, small-angle x-ray scattering, and
ultracentrifugation data of human and P. furiosus MRE11/RAD50 complex
revealed a dual functional complex consisting of a (MRE11)2/(RAD50)2
heterotetrameric DNA-processing head and a double coiled-coil linker.
The human RAD50/MRE11/NBS1 complex (R/M/N) has a dynamic molecular
architecture consisting of a globular DNA binding domain from which two
50-nanometer coiled coils protrude. The coiled coils are flexible and
their apices can self-associate. The flexibility of the coiled coils
allows their apices to adopt an orientation favorable for interaction.
However, this also allows interaction between the tips of the 2 coiled
coils within the same complex, which competes with and frustrates the
intercomplex interaction required for DNA tethering. Moreno-Herrero et
al. (2005) showed that the dynamic architecture of the R/M/N complex is
markedly affected by DNA binding. DNA binding by the R/M/N globular
domain leads to parallel orientation of the coiled coils; this prevents
intracomplex interactions and favors intercomplex associations needed
for DNA tethering. The R/M/N complex thus is an example of a biologic
nanomachine in which binding to its ligand, in this case DNA, affects
the functional conformation of a domain located 50 nanometers distant.
MAPPING
By analysis of somatic cell hybrids and by fluorescence in situ
hybridization, Petrini et al. (1995) mapped the MRE11 gene to 11q21. An
MRE11-related locus was found on 7q11.2-q11.3.
MOLECULAR GENETICS
In 2 families with ataxia-telangiectasia-like disorder (ATLD; 604391),
Stewart et al. (1999) identified mutations in the MRE11A gene.
Consistent with the clinical outcome of these mutations, cells
established from the affected individuals within the 2 families
exhibited many of the features characteristic of both
ataxia-telangiectasia (208900) and NBS, including chromosomal
instability, increased sensitivity to ionizing radiation, defective
induction of stress-activated signal transduction pathways, and
radioresistant DNA synthesis. These data strengthened the molecular
connection between double-stranded break recognition by the MRE11A/RAD50
(604040)/NBS1 (602667) protein complex and the ability of the cell to
activate the DNA damage-response pathway controlled by ATM (607585).
Delia et al. (2004) described 2 sibs with late-onset cerebellar
degeneration, absence of telangiectasia, and absence of malignancy
through their fourth decade. Both patients were compound heterozygotes
for MRE11 mutations (600814.0003 and 600814.0004). Lymphoblastoid cell
lines (LCLs) derived from these sibs exhibited normal ATM expression,
but were defective for MRE11, RAD50, and NBS1 protein expression.
Response to gamma-radiation was abnormal, as evident by the enhanced
radiosensitivity, attenuated autophosphorylation of serine-1981 on ATM
and phosphorylation of serine-15 on p53 (191170) and serine-966 on
SMC1A, failure to form Mre11 nuclear foci, and defective G1 checkpoint
arrest. Fibroblasts from the 2 sibs, but not LCLs, showed impaired
ATM-dependent Chk2 (CHEK2; 604373) phosphorylation.
Fernet et al. (2005) described 10 patients from 3 unrelated Saudi
Arabian families with ATLD. All patients were homozygous for a W210C
mutation (600814.0005) in the MRE11A gene. In fibroblast cultures
established from 2 individuals, there were high constitutive levels of
MRE11A and RAD50 proteins compared with controls but a very low level of
the NBS1 protein. After exposure to ionizing radiation, a dose-dependent
defect in ATM serine-1981, p53 serine-15 and Chek2 phosphorylation, and
p53 stabilization were noted, together with a failure to form MRE11A
foci and enhanced radiation sensitivity. Fernet et al. (2005)
hypothesized that the MRE11A/RAD50/NBS1 complex may act as a sensor of
DNA double-strand breaks, acting upstream of ATM.
*FIELD* AV
.0001
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, ARG633TER
In 2 first cousins with ataxia-telangiectasia-like disorder (ATLD;
604391) from a large inbred family from Pakistan originally reported by
Hernandez et al. (1993), Stewart et al. (1999) identified a homozygous
C-to-T transition at nucleotide 1897 of the MRE11A gene, resulting in an
arg633-to-ter (R633X) mutation. Both patients had progressive cerebellar
degeneration, but neither patient showed any intellectual impairment.
Chaki et al. (2012) identified a homozygous R633X mutation in 2 sibs,
born of consanguineous Pakistani parents, with ataxia and cerebellar
vermis hypoplasia. One patient had dysarthria and myoclonus. Although
the patients were part of a larger group of patients with
nephronophthisis (see, e.g., NPHP1, 256100) and related ciliopathies,
neither had renal failure or retinal involvement. The mutation was found
by homozygosity mapping and whole-exome sequencing. The report linked
the pathogenesis of NPHP and ciliopathy to defects in DNA damage
response signaling.
.0002
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, ASN117SER
In 2 brothers with ataxia-telangiectasia-like disorder (604391)
originally reported by Klein et al. (1996), Stewart et al. (1999)
identified a heterozygous A-to-G transition at nucleotide 350 of the
MRE11A gene, resulting in an asn117-to-ser (N117S) substitution on the
paternal allele. No maternally derived mutation was detected by DNA
sequencing, suggesting that the mother was heterozygous for a null
MRE11A mutation. Western blotting showed reduced MRE11A levels in
maternally-derived cells. The boys had early-childhood onset of
progressive cerebellar degeneration causing cerebellar ataxia and
oculomotor apraxia, but no telangiectasia. Pitts et al. (2001) later
identified a heterozygous truncating mutation in the MRE11A gene
(600814.0003) on the maternal allele. The findings confirmed autosomal
recessive inheritance of the disorder.
.0003
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, ARG571TER
In affected members of the family with ataxia-telangiectasia-like
disorder (604391) originally reported by Klein et al. (1996), in whom
Stewart et al. (1999) had identified a heterozygous missense mutation in
the MRE11A gene (600814.0002) on the paternal allele, Pitts et al.
(2001) identified a heterozygous 1714C-T transition in exon 15 of the
MRE11A gene, resulting in an arg571-to-ter (R571X) substitution on the
maternal allele. This maternally inherited mutant allele had not been
detected previously because transcripts derived from it underwent
nonsense-mediated mRNA decay.
.0004
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, THR481LYS
Delia et al. (2004) described 2 Italian sibs with late-onset cerebellar
degeneration that progressed slowly until puberty, absence of
telangiectasia, and absence of malignancy through their fourth decade
(604391). In both sibs, the authors identified compound heterozygosity
for the R571X mutation (600814.0003) and a 1422C-A transversion in exon
15 of the MRE11A gene, resulting in a thr481-to-lys (T481K)
substitution. The T481K mutation was maternally inherited, and the
paternal R571X allele was null as a result of NMD.
.0005
ATAXIA-TELANGIECTASIA-LIKE DISORDER
MRE11A, TRP210CYS
In 10 patients from 3 unrelated Saudi Arabian families with ATLD
(604391), Fernet et al. (2005) identified homozygosity for a 630G-C
transversion in exon 7 of the MRE11A gene, resulting in a trp210-to-cys
(W210C) substitution between motifs III and IV of the N-terminal
nuclease domain. Patients presented with an early-onset, slowly
progressive, ataxia plus ocular apraxia phenotype with an absence of
tumor development, even in the oldest 37-year-old patient.
Extraneurologic features, such as telangiectasia, raised
alpha-fetoprotein, and reduced immunoglobulin levels, were absent.
*FIELD* RF
1. Baumann, P.; West, S. C.: DNA end-joining catalyzed by human cell-free
extracts. Proc. Nat. Acad. Sci. 95: 14066-14070, 1998.
2. Boisvert, F.-M.; Dery, U.; Masson, J.-Y.; Richard, S.: Arginine
methylation of MRE11 by PRMT1 is required for DNA damage checkpoint
control. Genes Dev. 19: 671-676, 2005.
3. Carney, J. P.; Maser, R. S.; Olivares, H.; Davis, E. M.; Le Beau,
M.; Yates, J. R., III; Hays, L.; Morgan, W. F.; Petrini, J. H. J.
: The hMre11/hRad50 protein complex and Nijmegen breakage syndrome:
linkage of double-strand break repair to the cellular DNA damage response. Cell 93:
477-486, 1998.
4. Chaki, M.; Airik, R.; Ghosh, A. K.; Giles, R. H.; Chen, R.; Slaats,
G. G.; Wang, H.; Hurd, T. W.; Zhou, W.; Cluckey, A.; Gee, H. Y.; Ramaswami,
G.; and 61 others: Exome capture reveals ZNF423 and CEP164 mutations,
linking renal ciliopathies to DNA damage response signaling. Cell 150:
533-548, 2012.
5. Costanzo, V.; Robertson, K.; Bibikova, M.; Kim, E.; Grieco, D.;
Gottesman, M.; Carroll, D.; Gautier, J.: Mre11 protein complex prevents
double-strand break accumulation during chromosomal DNA replication. Molec.
Cell 8: 137-147, 2001.
6. Delia, D.; Piane, M.; Buscemi, G.; Savio, C.; Palmeri, S.; Lulli,
P.; Carlessi, L.; Fontanella, E.; Chessa, L.: MRE11 mutations and
impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like
disorder. Hum. Molec. Genet. 13: 2155-2163, 2004.
7. Deng, Y.; Guo, X.; Ferguson, D. O.; Chang, S.: Multiple roles
for MRE11 at uncapped telomeres. Nature 460: 914-918, 2009.
8. Falck, J.; Petrini, J. H. J.; Williams, B. R.; Lukas, J.; Bartek,
J.: The DNA damage-dependent intra-S phase checkpoint is regulated
by parallel pathways. Nature Genet. 30: 290-294, 2002.
9. Fernet, M.; Gribaa, M.; Salih, M. A. M.; Seidahmed, M. Z.; Hall,
J.; Koenig, M.: Identification and functional consequences of a novel
MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia
telangiectasia-like disorder. Hum. Molec. Genet. 14: 307-318, 2005.
10. Franchitto, A.; Pichierri, P.: Protecting genomic integrity during
DNA replication: correlation between Werner's and Bloom's syndrome
gene products and the MRE11 complex. Hum. Molec. Genet. 11: 2447-2453,
2002.
11. Garcia, V.; Phelps, S. E. L.; Gray, S.; Neale, M. J.: Bidirectional
resection of DNA double-strand breaks by Mre11 and Exo1. Nature 479:
241-244, 2011.
12. Goedecke, W.; Eijpe, M.; Offenberg, H. H.; van Aalderen, M.; Heyting,
C.: Mre11 and Ku70 interact in somatic cells, but are differentially
expressed in early meiosis. Nature Genet. 23: 194-198, 1999.
13. Hernandez, D.; McConville, C. M.; Stacey, M.; Woods, C. G.; Brown,
M. M.; Shutt, P.; Rysiecki, G.; Taylor, A. M. R.: A family showing
no evidence of linkage between the ataxia telangiectasia gene and
chromosome 1q22-23. J. Med. Genet. 30: 135-140, 1993.
14. Hopfner, K.-P.; Karcher, A.; Craig, L.; Woo, T. T.; Carney, J.
P.; Tainer, J. A.: Structural biochemistry and interaction architecture
of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase. Cell 105:
473-485, 2001.
15. Klein, C.; Wenning, G. K.; Quinn, N. P.; Marsden, C. D.: Ataxia
without telangiectasia masquerading as benign hereditary chorea. Mov.
Disord. 11: 217-220, 1996.
16. Larson, E. D.; Cummings, W. J.; Bednarski, D. W.; Maizels, N.
: MRE11/RAD50 cleaves DNA in the AID/UNG-dependent pathway of immunoglobulin
gene diversification. Molec. Cell 20: 367-375, 2005.
17. Moreno-Herrero, F.; de Jager, M.; Dekker, N. H.; Kanaar, R.; Wyman,
C.; Dekker, C.: Mesoscale conformational changes in the DNA-repair
complex Rad50/Mre11/Nbs1 upon binding DNA. Nature 437: 440-443,
2005.
18. Paull, T. T.; Gellert, M.: The 3-prime to 5-prime exonuclease
activity of Mre11 facilitates repair of DNA double-strand breaks. Molec.
Cell 1: 969-979, 1998.
19. Petrini, J. H. J.; Walsh, M. E.; DiMare, C.; Chen, X.-N.; Korenberg,
J. R.; Weaver, D. T.: Isolation and characterization of the human
MRE11 homologue. Genomics 29: 80-86, 1995.
20. Pitts, S. A.; Kullar, H. S.; Stankovic, T.; Stewart, G. S.; Last,
J. I. K.; Bedenham, T.; Armstrong, S. J.; Piane, M.; Chessa, L.; Taylor,
A. M. R.; Byrd, P. J.: hMRE11: genomic structure and a null mutation
identified in a transcript protected from nonsense-mediated mRNA decay. Hum.
Molec. Genet. 10: 1155-1162, 2001.
21. Stewart, G. S.; Maser, R. S.; Stankovic, T.; Bressan, D. A.; Kaplan,
M. I.; Jaspers, N. G. J.; Raams, A.; Byrd, P. J.; Petrini, J. H. J.;
Taylor, A. M. R.: The DNA double-strand break repair gene hMRE11
is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99:
577-587, 1999.
22. Stracker, T. H.; Carson, C. T.; Weitzman, M. D.: Adenovirus oncoproteins
inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature 418:
348-352, 2002.
23. Takata, M.; Sasaki, M. S.; Sonoda, E.; Morrison, C.; Hashimoto,
M.; Utsumi, H.; Yamaguchi-Iwai, Y.; Shinohara, A.; Takeda, S.: Homologous
recombination and non-homologous end-joining pathways of DNA double-strand
break repair have overlapping roles in the maintenance of chromosomal
integrity in vertebrate cells. EMBO J. 17: 5497-5508, 1998.
24. Trujillo, K. M.; Yuan, S.-S. F.; Lee, E. Y.-H. P.; Sung, P.:
Nuclease activities in a complex of human recombination and DNA repair
factors Rad50, Mre11, and p95. J. Biol. Chem. 273: 21447-21450,
1998.
25. Wang, Y.; Cortez, D.; Yazdi, P.; Neff, N.; Elledge, S. J.; Qin,
J.: BASC, a super complex of BRCA1-associated proteins involved in
the recognition and repair of aberrant DNA structures. Genes Dev. 14:
927-939, 2000.
26. Zhong, H.; Bryson, A.; Eckersdorff, M.; Ferguson, D. O.: Rad50
depletion impacts upon ATR-dependent DNA damage responses. Hum. Molec.
Genet. 14: 2685-2693, 2005.
27. Zhong, Q.; Chen, C.-F.; Li, S.; Chen, Y.; Wang, C.-C.; Xiao, J.;
Chen, P.-L.; Sharp, Z. D.; Lee, W.-H.: Association of BRCA1 with
the hRad50-hMre11-p95 complex and the DNA damage response. Science 285:
747-750, 1999.
28. Zhu, X.-D.; Kuster, B.; Mann, M.; Petrini, J. H. J.; de Lange,
T.: Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2
and human telomeres. Nature Genet. 25: 347-352, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 10/4/2012
Ada Hamosh - updated: 12/21/2011
Ada Hamosh - updated: 9/4/2009
George E. Tiller - updated: 12/10/2008
George E. Tiller - updated: 11/8/2007
George E. Tiller - updated: 3/21/2007
Paul J. Converse - updated: 2/9/2006
Ada Hamosh - updated: 11/3/2005
Patricia A. Hartz - updated: 4/19/2005
George E. Tiller - updated: 12/4/2003
Ada Hamosh - updated: 7/24/2002
Ada Hamosh - updated: 3/28/2002
Stylianos E. Antonarakis - updated: 8/3/2001
Stylianos E. Antonarakis - updated: 6/4/2001
Paul J. Converse - updated: 11/16/2000
Victor A. McKusick - updated: 6/27/2000
Stylianos E. Antonarakis - updated: 12/29/1999
Victor A. McKusick - updated: 9/28/1999
Ada Hamosh - updated: 7/30/1999
Rebekah S. Rasooly - updated: 7/22/1999
Stylianos E. Antonarakis - updated: 8/3/1998
*FIELD* CD
Victor A. McKusick: 10/2/1995
*FIELD* ED
carol: 10/08/2012
terry: 10/5/2012
ckniffin: 10/4/2012
alopez: 1/5/2012
terry: 12/21/2011
alopez: 9/8/2009
terry: 9/4/2009
wwang: 12/10/2008
wwang: 12/3/2007
terry: 11/8/2007
wwang: 3/26/2007
terry: 3/21/2007
mgross: 2/9/2006
alopez: 11/7/2005
terry: 11/3/2005
mgross: 4/21/2005
terry: 4/19/2005
mgross: 4/14/2005
mgross: 12/4/2003
ckniffin: 3/11/2003
alopez: 11/14/2002
cwells: 7/26/2002
terry: 7/24/2002
carol: 3/29/2002
cwells: 3/29/2002
terry: 3/28/2002
cwells: 10/30/2001
cwells: 10/16/2001
mgross: 8/3/2001
mgross: 6/4/2001
joanna: 1/17/2001
mgross: 11/16/2000
alopez: 6/27/2000
mgross: 1/3/2000
mgross: 12/29/1999
terry: 12/1/1999
alopez: 9/30/1999
terry: 9/28/1999
alopez: 7/30/1999
mgross: 7/22/1999
carol: 8/20/1998
carol: 8/4/1998
terry: 8/3/1998
mark: 10/2/1995
MIM
604391
*RECORD*
*FIELD* NO
604391
*FIELD* TI
#604391 ATAXIA-TELANGIECTASIA-LIKE DISORDER; ATLD
*FIELD* TX
A number sign (#) is used with this entry because
read moreataxia-telangiectasia-like disorder (ATLD) is caused by homozygous or
compound heterozygous mutation in the MRE11A gene (600814) on chromosome
11q21.
DESCRIPTION
Ataxia-telangiectasia-like disorder is an autosomal recessive disorder
characterized clinically by progressive cerebellar degeneration
resulting in ataxia and oculomotor apraxia. Laboratory studies of
patient cells showed increased susceptibility to radiation, consistent
with a defect in DNA repair. The disorder shares some phenotypic
features of ataxia-telangiectasia (AT; 208900), but telangiectases and
immune deficiency are not present in ATLD (summary by Hernandez et al.,
1993 and Stewart et al., 1999).
CLINICAL FEATURES
Hernandez et al. (1993) reported a large inbred family in which 2
cousins presented with the same clinical features of
ataxia-telangiectasia but with a somewhat milder clinical course. Both
patients were still ambulatory at ages 25 and 20 years. Cellular
features of both patients were typical of AT and included increased
radiosensitivity and an increased level of spontaneously occurring
chromosome aberrations in peripheral blood lymphocytes.
Delia et al. (2004) reported 2 Italian sibs with late-onset cerebellar
degeneration that progressed slowly until puberty. The sibs had no
telangiectasia or malignancy through their fourth decade.
Fernet et al. (2005) described 10 patients from 3 unrelated Saudi
Arabian families with ataxia telangiectasia-like disorder. They
presented with an early-onset, slowly progressive ataxia plus ocular
apraxia phenotype with an absence of tumor development, even in the
oldest, 37-year-old patient. Extraneurologic features, such as
telangiectasia, raised alpha-fetoprotein, and reduced immunoglobulin
levels, were absent. All patients were homozygous for a missense
mutation (600814.0005) in the MRE11A gene.
Chaki et al. (2012) reported 2 sibs, born of consanguineous Pakistani
parents, with ataxia and cerebellar vermis hypoplasia. One patient had
dysarthria and myoclonus. Although the patients studied were part of a
larger group of patients with nephronophthisis (see, e.g., NPHP1,
256100) and related ciliopathies, neither sib had renal failure or
retinal involvement. Chaki et al. (2012) noted that cerebellar vermis
hypoplasia is a cardinal feature of NPHP-related ciliopathies.
INHERITANCE
The transmission pattern in the family with ATLD reported by Hernandez
et al. (1993) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 2 families clinically diagnosed with AT and previously reported by
Hernandez et al. (1993) and Klein et al. (1996), respectively, Stewart
et al. (1999) identified mutations in the MRE11A gene (600814.0001 and
600814.0002). Consistent with the clinical outcome of these mutations,
cells established from the affected individuals within the 2 families
exhibited many of the features characteristic of both AT and Nijmegen
breakage syndrome (251260), including chromosomal instability, increased
sensitivity to ionizing radiation, defective induction of
stress-activated signal transduction pathways, and radioresistant DNA
synthesis. The authors designated the disorder ATLD, for AT-like
disorder. Because the MRE11A gene maps to 11q21 and the gene mutated in
AT, ATM, maps to 11q23, Stewart et al. (1999) concluded that only a very
detailed linkage analysis would separate ATLD from AT purely on the
basis of genetic data. Assuming that the mutation rate is proportional
to the length of the coding sequences of the 2 genes, they suggested
that approximately 6% of AT cases might be expected to have MRE11A
mutations.
In the English family with ataxia-telangiectasia-like disorder
originally reported by Klein et al. (1996), Pitts et al. (2001)
identified a second mutation in the MRE11A gene (600814.0003).
In 2 Italian sibs with ATLD, Delia et al. (2004) identified compound
heterozygosity for MRE11A mutations (600814.0003 and 600814.0004).
In 2 Pakistani sibs with ataxia and cerebellar vermis hypoplasia, Chaki
et al. (2012) identified a homozygous mutation in the MRE11A gene
(600814.0001). The mutation was found by homozygosity mapping and
whole-exome sequencing. The report linked the pathogenesis of NPHP and
ciliopathy to defects in DNA damage response signaling.
*FIELD* RF
1. Chaki, M.; Airik, R.; Ghosh, A. K.; Giles, R. H.; Chen, R.; Slaats,
G. G.; Wang, H.; Hurd, T. W.; Zhou, W.; Cluckey, A.; Gee, H. Y.; Ramaswami,
G.; and 61 others: Exome capture reveals ZNF423 and CEP164 mutations,
linking renal ciliopathies to DNA damage response signaling. Cell 150:
533-548, 2012.
2. Delia, D.; Piane, M.; Buscemi, G.; Savio, C.; Palmeri, S.; Lulli,
P.; Carlessi, L.; Fontanella, E.; Chessa, L.: MRE11 mutations and
impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia
-like disorder. Hum. Molec. Genet. 13: 2155-2163, 2004.
3. Fernet, M.; Gribaa, M.; Salih, M. A. M.; Seidahmed, M. Z.; Hall,
J.; Koenig, M.: Identification and functional consequences of a novel
MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia
telangiectasia-like disorder. Hum. Molec. Genet. 14: 307-318, 2005.
4. Hernandez, D.; McConville, C. M.; Stacey, M.; Woods, C. G.; Brown,
M. M.; Shutt, P.; Rysiecki, G.; Taylor, A. M. R.: A family showing
no evidence of linkage between the ataxia telangiectasia gene and
chromosome 1q22-23. J. Med. Genet. 30: 135-140, 1993.
5. Klein, C.; Wenning, G. K.; Quinn, N. P.; Marsden, C. D.: Ataxia
without telangiectasia masquerading as benign hereditary chorea. Mov.
Disord. 11: 217-220, 1996.
6. Pitts, S. A.; Kullar, H. S.; Stankovic, T.; Stewart, G. S.; Last,
J. I. K.; Bedenham, T.; Armstrong, S. J.; Piane, M.; Chessa, L.; Taylor,
A. M. R.; Byrd, P. J.: hMRE11: genomic structure and a null mutation
identified in a transcript protected from nonsense-mediated mRNA decay. Hum.
Molec. Genet. 10: 1155-1162, 2001.
7. Stewart, G. S.; Maser, R. S.; Stankovic, T.; Bressan, D. A.; Kaplan,
M. I.; Jaspers, N. G. J.; Raams, A.; Byrd, P. J.; Petrini, J. H. J.;
Taylor, A. M. R.: The DNA double-strand break repair gene hMRE11
is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99:
577-587, 1999.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Oculomotor apraxia;
Gaze-evoked nystagmus;
Impaired smooth pursuit;
Hypometric saccades
MUSCLE, SOFT TISSUE:
Distal muscle wasting, mild
NEUROLOGIC:
[Central nervous system];
Gait ataxia;
Frequent falls;
Chorea;
Lower limb spasticity, mild;
Dystonia;
Dysarthria;
Dysdiadochokinesis;
Cerebellar degeneration, progressive;
Cerebellar atrophy;
[Peripheral nervous system];
Hyporeflexia
LABORATORY ABNORMALITIES:
Cells show increased sensitivity to ionizing radiation;
Defective DNA repair;
Chromosomal instability
MISCELLANEOUS:
Onset in early childhood;
Progressive disorder
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. Cerevisiae meiotic recombination
11 A gene (MRE11A, 600814.0001)
*FIELD* CD
Cassandra L. Kniffin: 10/2/2012
*FIELD* ED
joanna: 11/30/2012
ckniffin: 10/4/2012
*FIELD* CN
Cassandra L. Kniffin - updated: 10/4/2012
George E. Tiller - updated: 11/8/2007
George E. Tiller - updated: 3/26/2007
*FIELD* CD
Stylianos E. Antonarakis: 12/29/1999
*FIELD* ED
carol: 10/08/2012
terry: 10/5/2012
ckniffin: 10/4/2012
wwang: 12/3/2007
terry: 11/8/2007
wwang: 3/26/2007
mgross: 1/3/2000
mgross: 12/29/1999
*RECORD*
*FIELD* NO
604391
*FIELD* TI
#604391 ATAXIA-TELANGIECTASIA-LIKE DISORDER; ATLD
*FIELD* TX
A number sign (#) is used with this entry because
read moreataxia-telangiectasia-like disorder (ATLD) is caused by homozygous or
compound heterozygous mutation in the MRE11A gene (600814) on chromosome
11q21.
DESCRIPTION
Ataxia-telangiectasia-like disorder is an autosomal recessive disorder
characterized clinically by progressive cerebellar degeneration
resulting in ataxia and oculomotor apraxia. Laboratory studies of
patient cells showed increased susceptibility to radiation, consistent
with a defect in DNA repair. The disorder shares some phenotypic
features of ataxia-telangiectasia (AT; 208900), but telangiectases and
immune deficiency are not present in ATLD (summary by Hernandez et al.,
1993 and Stewart et al., 1999).
CLINICAL FEATURES
Hernandez et al. (1993) reported a large inbred family in which 2
cousins presented with the same clinical features of
ataxia-telangiectasia but with a somewhat milder clinical course. Both
patients were still ambulatory at ages 25 and 20 years. Cellular
features of both patients were typical of AT and included increased
radiosensitivity and an increased level of spontaneously occurring
chromosome aberrations in peripheral blood lymphocytes.
Delia et al. (2004) reported 2 Italian sibs with late-onset cerebellar
degeneration that progressed slowly until puberty. The sibs had no
telangiectasia or malignancy through their fourth decade.
Fernet et al. (2005) described 10 patients from 3 unrelated Saudi
Arabian families with ataxia telangiectasia-like disorder. They
presented with an early-onset, slowly progressive ataxia plus ocular
apraxia phenotype with an absence of tumor development, even in the
oldest, 37-year-old patient. Extraneurologic features, such as
telangiectasia, raised alpha-fetoprotein, and reduced immunoglobulin
levels, were absent. All patients were homozygous for a missense
mutation (600814.0005) in the MRE11A gene.
Chaki et al. (2012) reported 2 sibs, born of consanguineous Pakistani
parents, with ataxia and cerebellar vermis hypoplasia. One patient had
dysarthria and myoclonus. Although the patients studied were part of a
larger group of patients with nephronophthisis (see, e.g., NPHP1,
256100) and related ciliopathies, neither sib had renal failure or
retinal involvement. Chaki et al. (2012) noted that cerebellar vermis
hypoplasia is a cardinal feature of NPHP-related ciliopathies.
INHERITANCE
The transmission pattern in the family with ATLD reported by Hernandez
et al. (1993) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 2 families clinically diagnosed with AT and previously reported by
Hernandez et al. (1993) and Klein et al. (1996), respectively, Stewart
et al. (1999) identified mutations in the MRE11A gene (600814.0001 and
600814.0002). Consistent with the clinical outcome of these mutations,
cells established from the affected individuals within the 2 families
exhibited many of the features characteristic of both AT and Nijmegen
breakage syndrome (251260), including chromosomal instability, increased
sensitivity to ionizing radiation, defective induction of
stress-activated signal transduction pathways, and radioresistant DNA
synthesis. The authors designated the disorder ATLD, for AT-like
disorder. Because the MRE11A gene maps to 11q21 and the gene mutated in
AT, ATM, maps to 11q23, Stewart et al. (1999) concluded that only a very
detailed linkage analysis would separate ATLD from AT purely on the
basis of genetic data. Assuming that the mutation rate is proportional
to the length of the coding sequences of the 2 genes, they suggested
that approximately 6% of AT cases might be expected to have MRE11A
mutations.
In the English family with ataxia-telangiectasia-like disorder
originally reported by Klein et al. (1996), Pitts et al. (2001)
identified a second mutation in the MRE11A gene (600814.0003).
In 2 Italian sibs with ATLD, Delia et al. (2004) identified compound
heterozygosity for MRE11A mutations (600814.0003 and 600814.0004).
In 2 Pakistani sibs with ataxia and cerebellar vermis hypoplasia, Chaki
et al. (2012) identified a homozygous mutation in the MRE11A gene
(600814.0001). The mutation was found by homozygosity mapping and
whole-exome sequencing. The report linked the pathogenesis of NPHP and
ciliopathy to defects in DNA damage response signaling.
*FIELD* RF
1. Chaki, M.; Airik, R.; Ghosh, A. K.; Giles, R. H.; Chen, R.; Slaats,
G. G.; Wang, H.; Hurd, T. W.; Zhou, W.; Cluckey, A.; Gee, H. Y.; Ramaswami,
G.; and 61 others: Exome capture reveals ZNF423 and CEP164 mutations,
linking renal ciliopathies to DNA damage response signaling. Cell 150:
533-548, 2012.
2. Delia, D.; Piane, M.; Buscemi, G.; Savio, C.; Palmeri, S.; Lulli,
P.; Carlessi, L.; Fontanella, E.; Chessa, L.: MRE11 mutations and
impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia
-like disorder. Hum. Molec. Genet. 13: 2155-2163, 2004.
3. Fernet, M.; Gribaa, M.; Salih, M. A. M.; Seidahmed, M. Z.; Hall,
J.; Koenig, M.: Identification and functional consequences of a novel
MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia
telangiectasia-like disorder. Hum. Molec. Genet. 14: 307-318, 2005.
4. Hernandez, D.; McConville, C. M.; Stacey, M.; Woods, C. G.; Brown,
M. M.; Shutt, P.; Rysiecki, G.; Taylor, A. M. R.: A family showing
no evidence of linkage between the ataxia telangiectasia gene and
chromosome 1q22-23. J. Med. Genet. 30: 135-140, 1993.
5. Klein, C.; Wenning, G. K.; Quinn, N. P.; Marsden, C. D.: Ataxia
without telangiectasia masquerading as benign hereditary chorea. Mov.
Disord. 11: 217-220, 1996.
6. Pitts, S. A.; Kullar, H. S.; Stankovic, T.; Stewart, G. S.; Last,
J. I. K.; Bedenham, T.; Armstrong, S. J.; Piane, M.; Chessa, L.; Taylor,
A. M. R.; Byrd, P. J.: hMRE11: genomic structure and a null mutation
identified in a transcript protected from nonsense-mediated mRNA decay. Hum.
Molec. Genet. 10: 1155-1162, 2001.
7. Stewart, G. S.; Maser, R. S.; Stankovic, T.; Bressan, D. A.; Kaplan,
M. I.; Jaspers, N. G. J.; Raams, A.; Byrd, P. J.; Petrini, J. H. J.;
Taylor, A. M. R.: The DNA double-strand break repair gene hMRE11
is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99:
577-587, 1999.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Oculomotor apraxia;
Gaze-evoked nystagmus;
Impaired smooth pursuit;
Hypometric saccades
MUSCLE, SOFT TISSUE:
Distal muscle wasting, mild
NEUROLOGIC:
[Central nervous system];
Gait ataxia;
Frequent falls;
Chorea;
Lower limb spasticity, mild;
Dystonia;
Dysarthria;
Dysdiadochokinesis;
Cerebellar degeneration, progressive;
Cerebellar atrophy;
[Peripheral nervous system];
Hyporeflexia
LABORATORY ABNORMALITIES:
Cells show increased sensitivity to ionizing radiation;
Defective DNA repair;
Chromosomal instability
MISCELLANEOUS:
Onset in early childhood;
Progressive disorder
MOLECULAR BASIS:
Caused by mutation in the homolog of the S. Cerevisiae meiotic recombination
11 A gene (MRE11A, 600814.0001)
*FIELD* CD
Cassandra L. Kniffin: 10/2/2012
*FIELD* ED
joanna: 11/30/2012
ckniffin: 10/4/2012
*FIELD* CN
Cassandra L. Kniffin - updated: 10/4/2012
George E. Tiller - updated: 11/8/2007
George E. Tiller - updated: 3/26/2007
*FIELD* CD
Stylianos E. Antonarakis: 12/29/1999
*FIELD* ED
carol: 10/08/2012
terry: 10/5/2012
ckniffin: 10/4/2012
wwang: 12/3/2007
terry: 11/8/2007
wwang: 3/26/2007
mgross: 1/3/2000
mgross: 12/29/1999