Full text data of RAD50
RAD50
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
DNA repair protein RAD50; hRAD50; 3.6.-.-
Note: presumably soluble (membrane word is not in UniProt keywords or features)
DNA repair protein RAD50; hRAD50; 3.6.-.-
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q92878
ID RAD50_HUMAN Reviewed; 1312 AA.
AC Q92878; B9EGF5; O43254; Q6GMT7; Q6P5X3; Q9UP86;
DT 01-FEB-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1997, sequence version 1.
DT 22-JAN-2014, entry version 125.
DE RecName: Full=DNA repair protein RAD50;
DE Short=hRAD50;
DE EC=3.6.-.-;
GN Name=RAD50;
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 1), INTERACTION WITH MRE11A, AND
RP TISSUE SPECIFICITY.
RX PubMed=8756642;
RA Dolganov G.M., Maser R.S., Novikov A., Tosto L., Chong S.,
RA Bressan D.A., Petrini J.H.J.;
RT "Human Rad50 is physically associated with human Mre11: identification
RT of a conserved multiprotein complex implicated in recombinational DNA
RT repair.";
RL Mol. Cell. Biol. 16:4832-4841(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3).
RX PubMed=10415333; DOI=10.1016/S0378-1119(99)00215-2;
RA Kim K.K., Shin B.A., Seo K.H., Kim P.N., Koh J.T., Kim J.H.,
RA Park B.R.;
RT "Molecular cloning and characterization of splice variants of human
RT RAD50 gene.";
RL Gene 235:59-67(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANTS GLU-616; ALA-697;
RP HIS-964 AND MET-973.
RC TISSUE=Testis;
RA Offenberg H.H.;
RL Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph;
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 [7]
RP FUNCTION IN DSB REPAIR, AND IDENTIFICATION IN THE MRN COMPLEX WITH
RP MRE11A AND NBN.
RX PubMed=9590181; DOI=10.1016/S0092-8674(00)81175-7;
RA Carney J.P., Maser R.S., Olivares H., Davis E.M., Le Beau M.,
RA Yates J.R. III, Hays L., Morgan W.F., Petrini J.H.J.;
RT "The hMre11/hRad50 protein complex and Nijmegen breakage syndrome:
RT linkage of double-strand break repair to the cellular DNA damage
RT response.";
RL Cell 93:477-486(1998).
RN [8]
RP FUNCTION IN DSB REPAIR, AND IDENTIFICATION IN THE MRN COMPLEX WITH
RP MRE11A AND NBN.
RX PubMed=9705271; DOI=10.1074/jbc.273.34.21447;
RA Trujillo K.M., Yuan S.-S.F., Lee E.Y.-H.P., Sung P.;
RT "Nuclease activities in a complex of human recombination and DNA
RT repair factors Rad50, Mre11, and p95.";
RL J. Biol. Chem. 273:21447-21450(1998).
RN [9]
RP FUNCTION, ATP-BINDING, AND MUTAGENESIS OF LYS-42 AND ASP-1231.
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 [10]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH BRCA1.
RX PubMed=10426999; DOI=10.1126/science.285.5428.747;
RA Zhong Q., Chen C.-F., Li S., Chen Y., Wang C.-C., Xiao J., Chen P.-L.,
RA Sharp Z.D., Lee W.-H.;
RT "Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA
RT damage response.";
RL Science 285:747-750(1999).
RN [11]
RP SUBCELLULAR LOCATION, AND IDENTIFICATION IN THE BASC COMPLEX WITH
RP BRCA1; MSH2; MSH6; MLH1; ATM; BLM; MRE11A AND NBN.
RX PubMed=10783165; DOI=10.1101/gad.827000;
RA Wang Y., Cortez D., Yazdi P., Neff N., Elledge S.J., Qin J.;
RT "BASC, a super complex of BRCA1-associated proteins involved in the
RT recognition and repair of aberrant DNA structures.";
RL Genes Dev. 14:927-939(2000).
RN [12]
RP IDENTIFICATION IN THE MRN COMPLEX WITH MRE11A AND NBN.
RX PubMed=10839544; DOI=10.1038/35013083;
RA Zhao S., Weng Y.-C., Yuan S.-S.F., Lin Y.-T., Hsu H.-C., Lin S.-C.,
RA Gerbino E., Song M.-H., Zdzienicka M.Z., Gatti R.A., Shay J.W.,
RA Ziv Y., Shiloh Y., Lee E.Y.-H.P.;
RT "Functional link between ataxia-telangiectasia and Nijmegen breakage
RT syndrome gene products.";
RL Nature 405:473-477(2000).
RN [13]
RP FUNCTION IN TELOMERES, IDENTIFICATION BY MASS SPECTROMETRY, AND
RP IDENTIFICATION IN THE A COMPLEX WITH TERF2.
RX PubMed=10888888; DOI=10.1038/77139;
RA Zhu X.-D., Kuester B., Mann M., Petrini J.H.J., de Lange T.;
RT "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and
RT human telomeres.";
RL Nat. Genet. 25:347-352(2000).
RN [14]
RP INTERACTION WITH RINT1.
RX PubMed=11096100; DOI=10.1074/jbc.M008893200;
RA Xiao J., Liu C.-C., Chen P.-L., Lee W.-H.;
RT "RINT-1, a novel Rad50-interacting protein, participates in radiation-
RT induced G2/M checkpoint control.";
RL J. Biol. Chem. 276:6105-6111(2001).
RN [15]
RP FUNCTION, AND INTRAMOLECULAR COILED-COIL DOMAINS.
RX PubMed=11741547; DOI=10.1016/S1097-2765(01)00381-1;
RA de Jager M., van Noort J., van Gent D.C., Dekker C., Kanaar R.,
RA Wyman C.;
RT "Human Rad50/Mre11 is a flexible complex that can tether DNA ends.";
RL Mol. Cell 8:1129-1135(2001).
RN [16]
RP INACTIVATION BY ADENOVIRUS ONCOPROTEINS.
RX PubMed=12124628; DOI=10.1038/nature00863;
RA Stracker T.H., Carson C.T., Weitzman M.D.;
RT "Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair
RT complex.";
RL Nature 418:348-352(2002).
RN [17]
RP ATP-BINDING.
RX PubMed=12384589; DOI=10.1093/nar/gkf574;
RA de Jager M., Wyman C., van Gent D.C., Kanaar R.;
RT "DNA end-binding specificity of human Rad50/Mre11 is influenced by
RT ATP.";
RL Nucleic Acids Res. 30:4425-4431(2002).
RN [18]
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 [19]
RP FUNCTION IN ATM ACTIVATION.
RX PubMed=15064416; DOI=10.1126/science.1091496;
RA Lee J.-H., Paull T.T.;
RT "Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1
RT complex.";
RL Science 304:93-96(2004).
RN [20]
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 [21]
RP 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 [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635, AND MASS
RP SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635 AND THR-690, AND
RP 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 [24]
RP INVOLVEMENT IN NBSLD.
RX PubMed=19409520; DOI=10.1016/j.ajhg.2009.04.010;
RA Waltes R., Kalb R., Gatei M., Kijas A.W., Stumm M., Sobeck A.,
RA Wieland B., Varon R., Lerenthal Y., Lavin M.F., Schindler D.,
RA Doerk T.;
RT "Human RAD50 deficiency in a Nijmegen breakage syndrome-like
RT disorder.";
RL Am. J. Hum. Genet. 84:605-616(2009).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-690, AND MASS
RP 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 [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-959, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635 AND THR-690, 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 [28]
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 [29]
RP VARIANTS LEU-94 AND HIS-224.
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).
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: Binds 1 zinc ion per homodimer (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. Found in a complex with TERF2. Interacts
CC with RINT1. Interacts with BRCA1 via its N-terminal domain.
CC Interacts with DCLRE1C/Artemis.
CC -!- SUBCELLULAR LOCATION: Nucleus. Chromosome, telomere.
CC Note=Localizes to discrete nuclear foci after treatment with
CC genotoxic agents.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=RAD50-1, RAD50-2;
CC IsoId=Q92878-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q92878-2; Sequence=VSP_012591;
CC Name=3; Synonyms=RAD50-3;
CC IsoId=Q92878-3; Sequence=VSP_012590;
CC -!- TISSUE SPECIFICITY: Expressed at very low level in most tissues,
CC except in testis where it is expressed at higher level. Expressed
CC in fibroblasts.
CC -!- DOMAIN: The zinc-hook, which separates the large intramolecular
CC coiled coil regions, contains 2 Cys residues that coordinate one
CC molecule of zinc with the help of the 2 Cys residues of the zinc-
CC hook of another RAD50 molecule, thereby forming a V-shaped
CC homodimer. The two heads of the homodimer, which constitute the
CC ATP-binding domain, interact with the MRE11A homodimer (By
CC similarity).
CC -!- DISEASE: Nijmegen breakage syndrome-like disorder (NBSLD)
CC [MIM:613078]: A disorder similar to Nijmegen breakage syndrome and
CC characterized by chromosomal instability, radiation sensitivity,
CC microcephaly, growth retardation, short stature and bird-like
CC face. Immunodeficiency is absent. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
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 SMC family. RAD50 subfamily.
CC -!- SIMILARITY: Contains 1 zinc-hook domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH62603.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence;
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DR EMBL; U63139; AAB07119.1; -; mRNA.
DR EMBL; AF057299; AAD50325.1; -; mRNA.
DR EMBL; AF057300; AAD50326.1; -; mRNA.
DR EMBL; Z75311; CAA99729.1; -; mRNA.
DR EMBL; AC116366; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC004042; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW62329.1; -; Genomic_DNA.
DR EMBL; BC062603; AAH62603.1; ALT_SEQ; mRNA.
DR EMBL; BC073850; AAH73850.1; -; mRNA.
DR EMBL; BC136436; AAI36437.1; -; mRNA.
DR RefSeq; NP_005723.2; NM_005732.3.
DR UniGene; Hs.633509; -.
DR ProteinModelPortal; Q92878; -.
DR SMR; Q92878; 30-60, 1202-1274.
DR DIP; DIP-33606N; -.
DR IntAct; Q92878; 24.
DR MINT; MINT-100363; -.
DR STRING; 9606.ENSP00000265335; -.
DR PhosphoSite; Q92878; -.
DR DMDM; 60392986; -.
DR PaxDb; Q92878; -.
DR PRIDE; Q92878; -.
DR Ensembl; ENST00000265335; ENSP00000265335; ENSG00000113522.
DR Ensembl; ENST00000378823; ENSP00000368100; ENSG00000113522.
DR GeneID; 10111; -.
DR KEGG; hsa:10111; -.
DR UCSC; uc003kxh.3; human.
DR CTD; 10111; -.
DR GeneCards; GC05P131920; -.
DR HGNC; HGNC:9816; RAD50.
DR HPA; CAB022103; -.
DR HPA; CAB024979; -.
DR MIM; 604040; gene.
DR MIM; 613078; phenotype.
DR neXtProt; NX_Q92878; -.
DR Orphanet; 145; Hereditary breast and ovarian cancer syndrome.
DR Orphanet; 240760; Nijmegen breakage syndrome-like disorder.
DR PharmGKB; PA34175; -.
DR eggNOG; COG0419; -.
DR HOGENOM; HOG000090195; -.
DR HOVERGEN; HBG058033; -.
DR InParanoid; Q92878; -.
DR KO; K10866; -.
DR OMA; SLGSYVH; -.
DR OrthoDB; EOG725DGM; -.
DR Reactome; REACT_111183; Meiosis.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_216; DNA Repair.
DR ChiTaRS; RAD50; human.
DR GeneWiki; Rad50; -.
DR GenomeRNAi; 10111; -.
DR NextBio; 38249; -.
DR PRO; PR:Q92878; -.
DR ArrayExpress; Q92878; -.
DR Bgee; Q92878; -.
DR CleanEx; HS_RAD50; -.
DR Genevestigator; Q92878; -.
DR GO; GO:0030870; C:Mre11 complex; IDA:UniProtKB.
DR GO; GO:0000784; C:nuclear chromosome, telomeric region; IDA:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0045120; C:pronucleus; IEA:Ensembl.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003677; F:DNA binding; IDA:BHF-UCL.
DR GO; GO:0004518; F:nuclease activity; IEA:InterPro.
DR GO; GO:0030674; F:protein binding, bridging; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
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:0090305; P:nucleic acid phosphodiester bond hydrolysis; IEA:GOC.
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:0007131; P:reciprocal meiotic recombination; TAS:ProtInc.
DR GO; GO:0000019; P:regulation of mitotic recombination; IDA:UniProtKB.
DR GO; GO:0007004; P:telomere maintenance via telomerase; IDA:UniProtKB.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR004584; Rad50_eukaryotes.
DR InterPro; IPR007517; Rad50_Zn_hook.
DR InterPro; IPR013134; Zn_hook_Rad50.
DR PANTHER; PTHR18867; PTHR18867; 1.
DR Pfam; PF04423; Rad50_zn_hook; 1.
DR SUPFAM; SSF52540; SSF52540; 3.
DR TIGRFAMs; TIGR00606; rad50; 1.
DR PROSITE; PS51131; ZN_HOOK; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; ATP-binding; Cell cycle;
KW Chromosome; Coiled coil; Complete proteome; DNA damage; DNA repair;
KW Hydrolase; Meiosis; Metal-binding; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome; Telomere; Zinc.
FT CHAIN 1 1312 DNA repair protein RAD50.
FT /FTId=PRO_0000138641.
FT DOMAIN 635 734 Zinc-hook.
FT NP_BIND 36 43 ATP (Potential).
FT COILED 228 359 Potential.
FT COILED 401 598 Potential.
FT COILED 635 673 Potential.
FT COILED 706 734 Potential.
FT COILED 789 1079 Potential.
FT COMPBIAS 1201 1238 Ala/Asp-rich (DA-box).
FT METAL 681 681 Zinc (By similarity).
FT METAL 684 684 Zinc (By similarity).
FT MOD_RES 635 635 Phosphoserine.
FT MOD_RES 690 690 Phosphothreonine.
FT MOD_RES 959 959 N6-acetyllysine.
FT VAR_SEQ 1 139 Missing (in isoform 3).
FT /FTId=VSP_012590.
FT VAR_SEQ 1 5 MSRIE -> MLIFSVRDMFA (in isoform 2).
FT /FTId=VSP_012591.
FT VARIANT 94 94 I -> L (in dbSNP:rs28903085).
FT /FTId=VAR_025526.
FT VARIANT 127 127 V -> I (in dbSNP:rs28903086).
FT /FTId=VAR_029168.
FT VARIANT 191 191 T -> I (in dbSNP:rs2230017).
FT /FTId=VAR_022085.
FT VARIANT 193 193 R -> W (in dbSNP:rs28903087).
FT /FTId=VAR_029169.
FT VARIANT 224 224 R -> H (in dbSNP:rs28903088).
FT /FTId=VAR_025527.
FT VARIANT 315 315 V -> L (in dbSNP:rs28903090).
FT /FTId=VAR_034436.
FT VARIANT 469 469 G -> A (in dbSNP:rs55653181).
FT /FTId=VAR_061779.
FT VARIANT 616 616 K -> E (in dbSNP:rs1047380).
FT /FTId=VAR_020958.
FT VARIANT 697 697 V -> A (in dbSNP:rs1047382).
FT /FTId=VAR_020959.
FT VARIANT 842 842 V -> A (in dbSNP:rs28903093).
FT /FTId=VAR_029170.
FT VARIANT 964 964 Y -> H (in dbSNP:rs1047386).
FT /FTId=VAR_020960.
FT VARIANT 973 973 K -> M (in dbSNP:rs1129482).
FT /FTId=VAR_020961.
FT VARIANT 1038 1038 R -> G (in dbSNP:rs1047387).
FT /FTId=VAR_020962.
FT MUTAGEN 42 42 K->N: Abolishes ability to degrade ATP.
FT MUTAGEN 1231 1231 D->A: Abolishes ability to degrade ATP.
FT CONFLICT 204 204 K -> E (in Ref. 3; CAA99729).
FT CONFLICT 723 723 E -> K (in Ref. 6; AAH62603/AAH73850).
FT CONFLICT 733 733 V -> A (in Ref. 3; CAA99729).
SQ SEQUENCE 1312 AA; 153892 MW; 1F208C3817FC41FC CRC64;
MSRIEKMSIL GVRSFGIEDK DKQIITFFSP LTILVGPNGA GKTTIIECLK YICTGDFPPG
TKGNTFVHDP KVAQETDVRA QIRLQFRDVN GELIAVQRSM VCTQKSKKTE FKTLEGVITR
TKHGEKVSLS SKCAEIDREM ISSLGVSKAV LNNVIFCHQE DSNWPLSEGK ALKQKFDEIF
SATRYIKALE TLRQVRQTQG QKVKEYQMEL KYLKQYKEKA CEIRDQITSK EAQLTSSKEI
VKSYENELDP LKNRLKEIEH NLSKIMKLDN EIKALDSRKK QMEKDNSELE EKMEKVFQGT
DEQLNDLYHN HQRTVREKER KLVDCHRELE KLNKESRLLN QEKSELLVEQ GRLQLQADRH
QEHIRARDSL IQSLATQLEL DGFERGPFSE RQIKNFHKLV RERQEGEAKT ANQLMNDFAE
KETLKQKQID EIRDKKTGLG RIIELKSEIL SKKQNELKNV KYELQQLEGS SDRILELDQE
LIKAERELSK AEKNSNVETL KMEVISLQNE KADLDRTLRK LDQEMEQLNH HTTTRTQMEM
LTKDKADKDE QIRKIKSRHS DELTSLLGYF PNKKQLEDWL HSKSKEINQT RDRLAKLNKE
LASSEQNKNH INNELKRKEE QLSSYEDKLF DVCGSQDFES DLDRLKEEIE KSSKQRAMLA
GATAVYSQFI TQLTDENQSC CPVCQRVFQT EAELQEVISD LQSKLRLAPD KLKSTESELK
KKEKRRDEML GLVPMRQSII DLKEKEIPEL RNKLQNVNRD IQRLKNDIEE QETLLGTIMP
EEESAKVCLT DVTIMERFQM ELKDVERKIA QQAAKLQGID LDRTVQQVNQ EKQEKQHKLD
TVSSKIELNR KLIQDQQEQI QHLKSTTNEL KSEKLQISTN LQRRQQLEEQ TVELSTEVQS
LYREIKDAKE QVSPLETTLE KFQQEKEELI NKKNTSNKIA QDKLNDIKEK VKNIHGYMKD
IENYIQDGKD DYKKQKETEL NKVIAQLSEC EKHKEKINED MRLMRQDIDT QKIQERWLQD
NLTLRKRNEE LKEVEEERKQ HLKEMGQMQV LQMKSEHQKL EENIDNIKRN HNLALGRQKG
YEEEIIHFKK ELREPQFRDA EEKYREMMIV MRTTELVNKD LDIYYKTLDQ AIMKFHSMKM
EEINKIIRDL WRSTYRGQDI EYIEIRSDAD ENVSASDKRR NYNYRVVMLK GDTALDMRGR
CSAGQKVLAS LIIRLALAET FCLNCGIIAL DEPTTNLDRE NIESLAHALV EIIKSRSQQR
NFQLLVITHD EDFVELLGRS EYVEKFYRIK KNIDQCSEIV KCSVSSLGFN VH
//
ID RAD50_HUMAN Reviewed; 1312 AA.
AC Q92878; B9EGF5; O43254; Q6GMT7; Q6P5X3; Q9UP86;
DT 01-FEB-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1997, sequence version 1.
DT 22-JAN-2014, entry version 125.
DE RecName: Full=DNA repair protein RAD50;
DE Short=hRAD50;
DE EC=3.6.-.-;
GN Name=RAD50;
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 1), INTERACTION WITH MRE11A, AND
RP TISSUE SPECIFICITY.
RX PubMed=8756642;
RA Dolganov G.M., Maser R.S., Novikov A., Tosto L., Chong S.,
RA Bressan D.A., Petrini J.H.J.;
RT "Human Rad50 is physically associated with human Mre11: identification
RT of a conserved multiprotein complex implicated in recombinational DNA
RT repair.";
RL Mol. Cell. Biol. 16:4832-4841(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3).
RX PubMed=10415333; DOI=10.1016/S0378-1119(99)00215-2;
RA Kim K.K., Shin B.A., Seo K.H., Kim P.N., Koh J.T., Kim J.H.,
RA Park B.R.;
RT "Molecular cloning and characterization of splice variants of human
RT RAD50 gene.";
RL Gene 235:59-67(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANTS GLU-616; ALA-697;
RP HIS-964 AND MET-973.
RC TISSUE=Testis;
RA Offenberg H.H.;
RL Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph;
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 [7]
RP FUNCTION IN DSB REPAIR, AND IDENTIFICATION IN THE MRN COMPLEX WITH
RP MRE11A AND NBN.
RX PubMed=9590181; DOI=10.1016/S0092-8674(00)81175-7;
RA Carney J.P., Maser R.S., Olivares H., Davis E.M., Le Beau M.,
RA Yates J.R. III, Hays L., Morgan W.F., Petrini J.H.J.;
RT "The hMre11/hRad50 protein complex and Nijmegen breakage syndrome:
RT linkage of double-strand break repair to the cellular DNA damage
RT response.";
RL Cell 93:477-486(1998).
RN [8]
RP FUNCTION IN DSB REPAIR, AND IDENTIFICATION IN THE MRN COMPLEX WITH
RP MRE11A AND NBN.
RX PubMed=9705271; DOI=10.1074/jbc.273.34.21447;
RA Trujillo K.M., Yuan S.-S.F., Lee E.Y.-H.P., Sung P.;
RT "Nuclease activities in a complex of human recombination and DNA
RT repair factors Rad50, Mre11, and p95.";
RL J. Biol. Chem. 273:21447-21450(1998).
RN [9]
RP FUNCTION, ATP-BINDING, AND MUTAGENESIS OF LYS-42 AND ASP-1231.
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 [10]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH BRCA1.
RX PubMed=10426999; DOI=10.1126/science.285.5428.747;
RA Zhong Q., Chen C.-F., Li S., Chen Y., Wang C.-C., Xiao J., Chen P.-L.,
RA Sharp Z.D., Lee W.-H.;
RT "Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA
RT damage response.";
RL Science 285:747-750(1999).
RN [11]
RP SUBCELLULAR LOCATION, AND IDENTIFICATION IN THE BASC COMPLEX WITH
RP BRCA1; MSH2; MSH6; MLH1; ATM; BLM; MRE11A AND NBN.
RX PubMed=10783165; DOI=10.1101/gad.827000;
RA Wang Y., Cortez D., Yazdi P., Neff N., Elledge S.J., Qin J.;
RT "BASC, a super complex of BRCA1-associated proteins involved in the
RT recognition and repair of aberrant DNA structures.";
RL Genes Dev. 14:927-939(2000).
RN [12]
RP IDENTIFICATION IN THE MRN COMPLEX WITH MRE11A AND NBN.
RX PubMed=10839544; DOI=10.1038/35013083;
RA Zhao S., Weng Y.-C., Yuan S.-S.F., Lin Y.-T., Hsu H.-C., Lin S.-C.,
RA Gerbino E., Song M.-H., Zdzienicka M.Z., Gatti R.A., Shay J.W.,
RA Ziv Y., Shiloh Y., Lee E.Y.-H.P.;
RT "Functional link between ataxia-telangiectasia and Nijmegen breakage
RT syndrome gene products.";
RL Nature 405:473-477(2000).
RN [13]
RP FUNCTION IN TELOMERES, IDENTIFICATION BY MASS SPECTROMETRY, AND
RP IDENTIFICATION IN THE A COMPLEX WITH TERF2.
RX PubMed=10888888; DOI=10.1038/77139;
RA Zhu X.-D., Kuester B., Mann M., Petrini J.H.J., de Lange T.;
RT "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and
RT human telomeres.";
RL Nat. Genet. 25:347-352(2000).
RN [14]
RP INTERACTION WITH RINT1.
RX PubMed=11096100; DOI=10.1074/jbc.M008893200;
RA Xiao J., Liu C.-C., Chen P.-L., Lee W.-H.;
RT "RINT-1, a novel Rad50-interacting protein, participates in radiation-
RT induced G2/M checkpoint control.";
RL J. Biol. Chem. 276:6105-6111(2001).
RN [15]
RP FUNCTION, AND INTRAMOLECULAR COILED-COIL DOMAINS.
RX PubMed=11741547; DOI=10.1016/S1097-2765(01)00381-1;
RA de Jager M., van Noort J., van Gent D.C., Dekker C., Kanaar R.,
RA Wyman C.;
RT "Human Rad50/Mre11 is a flexible complex that can tether DNA ends.";
RL Mol. Cell 8:1129-1135(2001).
RN [16]
RP INACTIVATION BY ADENOVIRUS ONCOPROTEINS.
RX PubMed=12124628; DOI=10.1038/nature00863;
RA Stracker T.H., Carson C.T., Weitzman M.D.;
RT "Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair
RT complex.";
RL Nature 418:348-352(2002).
RN [17]
RP ATP-BINDING.
RX PubMed=12384589; DOI=10.1093/nar/gkf574;
RA de Jager M., Wyman C., van Gent D.C., Kanaar R.;
RT "DNA end-binding specificity of human Rad50/Mre11 is influenced by
RT ATP.";
RL Nucleic Acids Res. 30:4425-4431(2002).
RN [18]
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 [19]
RP FUNCTION IN ATM ACTIVATION.
RX PubMed=15064416; DOI=10.1126/science.1091496;
RA Lee J.-H., Paull T.T.;
RT "Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1
RT complex.";
RL Science 304:93-96(2004).
RN [20]
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 [21]
RP 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 [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635, AND MASS
RP SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635 AND THR-690, AND
RP 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 [24]
RP INVOLVEMENT IN NBSLD.
RX PubMed=19409520; DOI=10.1016/j.ajhg.2009.04.010;
RA Waltes R., Kalb R., Gatei M., Kijas A.W., Stumm M., Sobeck A.,
RA Wieland B., Varon R., Lerenthal Y., Lavin M.F., Schindler D.,
RA Doerk T.;
RT "Human RAD50 deficiency in a Nijmegen breakage syndrome-like
RT disorder.";
RL Am. J. Hum. Genet. 84:605-616(2009).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-690, AND MASS
RP 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 [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-959, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635 AND THR-690, 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 [28]
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 [29]
RP VARIANTS LEU-94 AND HIS-224.
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).
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: Binds 1 zinc ion per homodimer (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. Found in a complex with TERF2. Interacts
CC with RINT1. Interacts with BRCA1 via its N-terminal domain.
CC Interacts with DCLRE1C/Artemis.
CC -!- SUBCELLULAR LOCATION: Nucleus. Chromosome, telomere.
CC Note=Localizes to discrete nuclear foci after treatment with
CC genotoxic agents.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=RAD50-1, RAD50-2;
CC IsoId=Q92878-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q92878-2; Sequence=VSP_012591;
CC Name=3; Synonyms=RAD50-3;
CC IsoId=Q92878-3; Sequence=VSP_012590;
CC -!- TISSUE SPECIFICITY: Expressed at very low level in most tissues,
CC except in testis where it is expressed at higher level. Expressed
CC in fibroblasts.
CC -!- DOMAIN: The zinc-hook, which separates the large intramolecular
CC coiled coil regions, contains 2 Cys residues that coordinate one
CC molecule of zinc with the help of the 2 Cys residues of the zinc-
CC hook of another RAD50 molecule, thereby forming a V-shaped
CC homodimer. The two heads of the homodimer, which constitute the
CC ATP-binding domain, interact with the MRE11A homodimer (By
CC similarity).
CC -!- DISEASE: Nijmegen breakage syndrome-like disorder (NBSLD)
CC [MIM:613078]: A disorder similar to Nijmegen breakage syndrome and
CC characterized by chromosomal instability, radiation sensitivity,
CC microcephaly, growth retardation, short stature and bird-like
CC face. Immunodeficiency is absent. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
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 SMC family. RAD50 subfamily.
CC -!- SIMILARITY: Contains 1 zinc-hook domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH62603.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence;
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DR EMBL; U63139; AAB07119.1; -; mRNA.
DR EMBL; AF057299; AAD50325.1; -; mRNA.
DR EMBL; AF057300; AAD50326.1; -; mRNA.
DR EMBL; Z75311; CAA99729.1; -; mRNA.
DR EMBL; AC116366; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC004042; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW62329.1; -; Genomic_DNA.
DR EMBL; BC062603; AAH62603.1; ALT_SEQ; mRNA.
DR EMBL; BC073850; AAH73850.1; -; mRNA.
DR EMBL; BC136436; AAI36437.1; -; mRNA.
DR RefSeq; NP_005723.2; NM_005732.3.
DR UniGene; Hs.633509; -.
DR ProteinModelPortal; Q92878; -.
DR SMR; Q92878; 30-60, 1202-1274.
DR DIP; DIP-33606N; -.
DR IntAct; Q92878; 24.
DR MINT; MINT-100363; -.
DR STRING; 9606.ENSP00000265335; -.
DR PhosphoSite; Q92878; -.
DR DMDM; 60392986; -.
DR PaxDb; Q92878; -.
DR PRIDE; Q92878; -.
DR Ensembl; ENST00000265335; ENSP00000265335; ENSG00000113522.
DR Ensembl; ENST00000378823; ENSP00000368100; ENSG00000113522.
DR GeneID; 10111; -.
DR KEGG; hsa:10111; -.
DR UCSC; uc003kxh.3; human.
DR CTD; 10111; -.
DR GeneCards; GC05P131920; -.
DR HGNC; HGNC:9816; RAD50.
DR HPA; CAB022103; -.
DR HPA; CAB024979; -.
DR MIM; 604040; gene.
DR MIM; 613078; phenotype.
DR neXtProt; NX_Q92878; -.
DR Orphanet; 145; Hereditary breast and ovarian cancer syndrome.
DR Orphanet; 240760; Nijmegen breakage syndrome-like disorder.
DR PharmGKB; PA34175; -.
DR eggNOG; COG0419; -.
DR HOGENOM; HOG000090195; -.
DR HOVERGEN; HBG058033; -.
DR InParanoid; Q92878; -.
DR KO; K10866; -.
DR OMA; SLGSYVH; -.
DR OrthoDB; EOG725DGM; -.
DR Reactome; REACT_111183; Meiosis.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_216; DNA Repair.
DR ChiTaRS; RAD50; human.
DR GeneWiki; Rad50; -.
DR GenomeRNAi; 10111; -.
DR NextBio; 38249; -.
DR PRO; PR:Q92878; -.
DR ArrayExpress; Q92878; -.
DR Bgee; Q92878; -.
DR CleanEx; HS_RAD50; -.
DR Genevestigator; Q92878; -.
DR GO; GO:0030870; C:Mre11 complex; IDA:UniProtKB.
DR GO; GO:0000784; C:nuclear chromosome, telomeric region; IDA:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0045120; C:pronucleus; IEA:Ensembl.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003677; F:DNA binding; IDA:BHF-UCL.
DR GO; GO:0004518; F:nuclease activity; IEA:InterPro.
DR GO; GO:0030674; F:protein binding, bridging; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
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:0090305; P:nucleic acid phosphodiester bond hydrolysis; IEA:GOC.
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:0007131; P:reciprocal meiotic recombination; TAS:ProtInc.
DR GO; GO:0000019; P:regulation of mitotic recombination; IDA:UniProtKB.
DR GO; GO:0007004; P:telomere maintenance via telomerase; IDA:UniProtKB.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR004584; Rad50_eukaryotes.
DR InterPro; IPR007517; Rad50_Zn_hook.
DR InterPro; IPR013134; Zn_hook_Rad50.
DR PANTHER; PTHR18867; PTHR18867; 1.
DR Pfam; PF04423; Rad50_zn_hook; 1.
DR SUPFAM; SSF52540; SSF52540; 3.
DR TIGRFAMs; TIGR00606; rad50; 1.
DR PROSITE; PS51131; ZN_HOOK; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; ATP-binding; Cell cycle;
KW Chromosome; Coiled coil; Complete proteome; DNA damage; DNA repair;
KW Hydrolase; Meiosis; Metal-binding; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome; Telomere; Zinc.
FT CHAIN 1 1312 DNA repair protein RAD50.
FT /FTId=PRO_0000138641.
FT DOMAIN 635 734 Zinc-hook.
FT NP_BIND 36 43 ATP (Potential).
FT COILED 228 359 Potential.
FT COILED 401 598 Potential.
FT COILED 635 673 Potential.
FT COILED 706 734 Potential.
FT COILED 789 1079 Potential.
FT COMPBIAS 1201 1238 Ala/Asp-rich (DA-box).
FT METAL 681 681 Zinc (By similarity).
FT METAL 684 684 Zinc (By similarity).
FT MOD_RES 635 635 Phosphoserine.
FT MOD_RES 690 690 Phosphothreonine.
FT MOD_RES 959 959 N6-acetyllysine.
FT VAR_SEQ 1 139 Missing (in isoform 3).
FT /FTId=VSP_012590.
FT VAR_SEQ 1 5 MSRIE -> MLIFSVRDMFA (in isoform 2).
FT /FTId=VSP_012591.
FT VARIANT 94 94 I -> L (in dbSNP:rs28903085).
FT /FTId=VAR_025526.
FT VARIANT 127 127 V -> I (in dbSNP:rs28903086).
FT /FTId=VAR_029168.
FT VARIANT 191 191 T -> I (in dbSNP:rs2230017).
FT /FTId=VAR_022085.
FT VARIANT 193 193 R -> W (in dbSNP:rs28903087).
FT /FTId=VAR_029169.
FT VARIANT 224 224 R -> H (in dbSNP:rs28903088).
FT /FTId=VAR_025527.
FT VARIANT 315 315 V -> L (in dbSNP:rs28903090).
FT /FTId=VAR_034436.
FT VARIANT 469 469 G -> A (in dbSNP:rs55653181).
FT /FTId=VAR_061779.
FT VARIANT 616 616 K -> E (in dbSNP:rs1047380).
FT /FTId=VAR_020958.
FT VARIANT 697 697 V -> A (in dbSNP:rs1047382).
FT /FTId=VAR_020959.
FT VARIANT 842 842 V -> A (in dbSNP:rs28903093).
FT /FTId=VAR_029170.
FT VARIANT 964 964 Y -> H (in dbSNP:rs1047386).
FT /FTId=VAR_020960.
FT VARIANT 973 973 K -> M (in dbSNP:rs1129482).
FT /FTId=VAR_020961.
FT VARIANT 1038 1038 R -> G (in dbSNP:rs1047387).
FT /FTId=VAR_020962.
FT MUTAGEN 42 42 K->N: Abolishes ability to degrade ATP.
FT MUTAGEN 1231 1231 D->A: Abolishes ability to degrade ATP.
FT CONFLICT 204 204 K -> E (in Ref. 3; CAA99729).
FT CONFLICT 723 723 E -> K (in Ref. 6; AAH62603/AAH73850).
FT CONFLICT 733 733 V -> A (in Ref. 3; CAA99729).
SQ SEQUENCE 1312 AA; 153892 MW; 1F208C3817FC41FC CRC64;
MSRIEKMSIL GVRSFGIEDK DKQIITFFSP LTILVGPNGA GKTTIIECLK YICTGDFPPG
TKGNTFVHDP KVAQETDVRA QIRLQFRDVN GELIAVQRSM VCTQKSKKTE FKTLEGVITR
TKHGEKVSLS SKCAEIDREM ISSLGVSKAV LNNVIFCHQE DSNWPLSEGK ALKQKFDEIF
SATRYIKALE TLRQVRQTQG QKVKEYQMEL KYLKQYKEKA CEIRDQITSK EAQLTSSKEI
VKSYENELDP LKNRLKEIEH NLSKIMKLDN EIKALDSRKK QMEKDNSELE EKMEKVFQGT
DEQLNDLYHN HQRTVREKER KLVDCHRELE KLNKESRLLN QEKSELLVEQ GRLQLQADRH
QEHIRARDSL IQSLATQLEL DGFERGPFSE RQIKNFHKLV RERQEGEAKT ANQLMNDFAE
KETLKQKQID EIRDKKTGLG RIIELKSEIL SKKQNELKNV KYELQQLEGS SDRILELDQE
LIKAERELSK AEKNSNVETL KMEVISLQNE KADLDRTLRK LDQEMEQLNH HTTTRTQMEM
LTKDKADKDE QIRKIKSRHS DELTSLLGYF PNKKQLEDWL HSKSKEINQT RDRLAKLNKE
LASSEQNKNH INNELKRKEE QLSSYEDKLF DVCGSQDFES DLDRLKEEIE KSSKQRAMLA
GATAVYSQFI TQLTDENQSC CPVCQRVFQT EAELQEVISD LQSKLRLAPD KLKSTESELK
KKEKRRDEML GLVPMRQSII DLKEKEIPEL RNKLQNVNRD IQRLKNDIEE QETLLGTIMP
EEESAKVCLT DVTIMERFQM ELKDVERKIA QQAAKLQGID LDRTVQQVNQ EKQEKQHKLD
TVSSKIELNR KLIQDQQEQI QHLKSTTNEL KSEKLQISTN LQRRQQLEEQ TVELSTEVQS
LYREIKDAKE QVSPLETTLE KFQQEKEELI NKKNTSNKIA QDKLNDIKEK VKNIHGYMKD
IENYIQDGKD DYKKQKETEL NKVIAQLSEC EKHKEKINED MRLMRQDIDT QKIQERWLQD
NLTLRKRNEE LKEVEEERKQ HLKEMGQMQV LQMKSEHQKL EENIDNIKRN HNLALGRQKG
YEEEIIHFKK ELREPQFRDA EEKYREMMIV MRTTELVNKD LDIYYKTLDQ AIMKFHSMKM
EEINKIIRDL WRSTYRGQDI EYIEIRSDAD ENVSASDKRR NYNYRVVMLK GDTALDMRGR
CSAGQKVLAS LIIRLALAET FCLNCGIIAL DEPTTNLDRE NIESLAHALV EIIKSRSQQR
NFQLLVITHD EDFVELLGRS EYVEKFYRIK KNIDQCSEIV KCSVSSLGFN VH
//
MIM
604040
*RECORD*
*FIELD* NO
604040
*FIELD* TI
*604040 RAD50, S. CEREVISIAE, HOMOLOG OF; RAD50
*FIELD* TX
CLONING
The S. cerevisiae Rad50 gene encodes a protein that is essential for
read moredouble-stranded DNA break repair by nonhomologous DNA end joining and
chromosomal integration. The yeast Rad50, Mre11 (600814), and Xrs2
proteins appear to act in a multiprotein complex, consistent with the
observation that mutations in these genes confer nearly identical
phenotypes of no meiotic recombination and elevated rates of homologous
mitotic recombination. By direct selection of cDNAs from the 5q23-q31
chromosomal interval, Dolganov et al. (1996) isolated a cDNA encoding a
human Rad50 homolog. The human RAD50 gene spans 100 to 130 kb. Northern
blot analysis revealed that the RAD50 gene was expressed as a 5.5-kb
mRNA predominantly in testis. A faint 7-kb transcript, which the authors
considered to be an mRNA with an alternatively processed 3-prime end,
was also detected. Yeast Rad50 and the predicted 1,312-amino acid human
RAD50 protein share more than 50% identity in their N- and C-termini.
The central heptad repeat domains of the proteins have relatively
divergent primary sequences but are predicted to adopt very similar
coiled-coil structures. Using immunoprecipitation, Dolganov et al.
(1996) demonstrated that the 153-kD RAD50 is stably associated with
MRE11 in a protein complex, which may also include proteins of 95 kD,
200 kD, and 350 kD.
MAPPING
By inclusion within mapped clones and by analysis of somatic cell
hybrids, Dolganov et al. (1996) mapped the RAD50 gene to 5q31. They
suggested that a recombinational DNA repair deficiency may be associated
with the development of myeloid leukemia, since this chromosomal region
is frequently altered in acute myeloid leukemia and myelodysplastic
disease.
GENE FUNCTION
Trujillo et al. (1998) determined that the 95-kD protein in the
mammalian cell nuclear complex containing RAD50 and MRE11 is nibrin, or
p95 (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. They stated that
although p95 has little sequence homology to yeast Xrs2, the 2 proteins
can be considered functional analogs since they link the conserved
activities of MRE11/RAD50 to the cellular DNA damage response in their
respective organisms.
Zhong et al. (1999) showed that BRCA1 (113705) interacts in vitro and in
vivo 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.
Telomeres allow cells to distinguish natural chromosome ends from
damaged DNA and protect the ends from degradation and fusion. In human
cells, telomere protection depends on the TTAGGG repeat-binding factor,
TRF2 (602027), which may remodel telomeres into large duplex loops
(t-loops). Zhu et al. (2000) showed by nanoelectrospray tandem mass
spectrometry that RAD50 protein is present in TRF2 immunocomplexes.
Coimmunoprecipitation studies showed that a small fraction of RAD50,
MRE11, and p95 is associated with TRF2. Indirect immunofluorescence
demonstrated the presence of RAD50 and MRE11 at interphase telomeres.
NBS1 was associated with TRF2 and telomeres in S phase, but not in G1 or
G2. 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.
The MRE11/RAD50 protein complex functions in diverse aspects of the
cellular response to double strand breaks (DSBs), including the
detection of DNA damage, the activation of cell cycle checkpoints, and
DSB repair. Whereas genetic analyses in S. cerevisiae have provided
insight regarding DSB repair functions of this highly conserved complex,
the implication of the human complex in Nijmegen breakage syndrome
reveals its role in cell cycle checkpoint functions. Luo et al. (1999)
established mice with mutation in the mouse Rad50 gene and examined the
role of the Mre11/Rad50 protein complex in the DNA damage response.
Early embryonic cells deficient in Rad50 were hypersensitive to ionizing
radiation, consistent with a role for this complex in the repair of
ionizing radiation-induced DSBs. However, the null Rad50 mutation was
lethal in cultured embryonic stem cells and in early developing embryos,
indicating that the mammalian protein complex mediates functions in
normally growing cells that are essential for viability.
In mammalian cells, the conserved multiprotein MRN complex of MRE11,
RAD50, and NBS1 (602667) 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 concatamers too large to be packaged. Stracker et al. (2002)
investigated the cellular proteins involved in the concatamer formation
and how they are inactivated by E4 products during a wildtype infection.
They demonstrated that concatamerization 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
concatamerization. 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.
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.
Abuzeid et al. (2009) found that adenoviral-mediated transfection of a
mutant RAD50 gene into human squamous cell carcinoma cells disrupted the
MRN complex in a dominant-negative manner. The disruption significantly
downregulated MRN expression and enhanced the cytotoxicity of cisplatin
in vitro, with a corresponding increase in DNA damage and telomere
shortening. Treatment of nude mice with xenografts of
cisplatin-resistant human squamous cell cancer with this combination
therapy resulted in dramatic tumor regression with increased apoptosis
of tumor cells. The findings suggested that the use of targeted RAD50
disruption could be a chemosensitizing approach for cancer therapy in
the context of chemoresistance.
MOLECULAR GENETICS
In a patient with chromosome instability, x-ray hypersensitivity,
microcephaly, and growth retardation (Nijmegen breakage syndrome-like
disorder; 613078), Waltes et al. (2009) identified compound
heterozygosity in the RAD50 gene, for a nonsense mutation (604040.0001)
and a mutation at the natural stop codon leading to a 66-amino acid
extension (604040.0002). There was no detectable RNA or protein from the
allele carrying the nonsense mutation, whereas from the allele carrying
the extension mutation a small amount of RNA and protein could be
detected. Unlike patients with Nijmegen breakage syndrome (604391) and
MRE11 deficiency resulting in an ataxia-telangiectasia-like disorder
(604391), this patient with RAD50 deficiency did not have
immunodeficiency or malignancies. Cells from this patient were
intermediate in their radiosensitivity between wildtype and
ataxia-telangiectasia (208900) cells.
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.
Hopfner et al. (2002) presented a 2.2-angstrom crystal structure of the
Rad50 coiled-coil region that revealed an unexpected dimer interface at
the apex of the coiled coils in which pairs of conserved cys-x-x-cys
motifs form interlocking hooks that bind one zinc ion. Biochemical,
x-ray, and electron microscopy data indicated that these hooks can join
oppositely protruding Rad50 coiled-coil domains to form a flexible
bridge of up to 1,200 angstroms. This suggested a function for the long
insertion in the Rad50 ABC-ATPase. The Rad50 hook is functional, since
mutations in this motif confer radiation sensitivity in yeast and
disrupt binding at the distant Mre11 (600814) nuclease interface.
Hopfner et al. (2002) concluded that their data support an architectural
role for the Rad50 coiled coils in forming metal-mediated bridging
complexes between 2 DNA-binding heads. The resulting assemblies have
appropriate lengths and conformational properties to link sister
chromatids in homologous recombination and DNA ends in nonhomologous
end-joining.
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.
*FIELD* AV
.0001
NIJMEGEN BREAKAGE SYNDROME-LIKE DISORDER
RAD50, ARG1093TER
In a patient with Nijmegen breakage syndrome-like disorder (NBSLD;
613078), Waltes et al. (2009) identified compound heterozygosity for
mutations in the RAD50 gene. The maternal allele carried a C-to-T
transition at nucleotide 3277 in exon 21 of the RAD50 gene, resulting in
an arg-to-stop substitution at codon 1093 (R1093X). The paternal allele
carried a point mutation resulting in a 66-amino acid extension of the
protein (604040.0002). This mutation was associated with undetectable
RNA and protein and was not identified in 350 German chromosomes.
.0002
NIJMEGEN BREAKAGE SYNDROME-LIKE DISORDER
RAD50, TER1313TYR
In a patient with Nijmegen breakage syndrome-like disorder (NBSLD;
613078), Waltes et al. (2009) identified compound heterozygosity for
mutations in the RAD50 gene, for a nonsense mutation (604040.0001) and
an A-to-T transversion at nucleotide 3939, resulting in substitution of
the termination codon occurring at position 1313 with tyrosine at that
position and an extension of the reading frame by 66 amino acids
(X1313YextX*66). The prediction of a larger polypeptide produced by the
aberrant paternal allele was consistent with detection of a protein band
of increased molecular weight. Very low amounts of a larger polypeptide
detected by immunoblot analysis were considered a consequence either of
protein instability or unstable nonstop mRNA. This mutation was not
detected in 350 chromosomes from a German random population sample.
*FIELD* RF
1. Abuzeid, W. M.; Jiang, X.; Shi, G.; Wang, H.; Paulson, D.; Araki,
K.; Jungreis, D.; Carney, J.; O'Malley, B. W., Jr.; Li, D.: Molecular
disruption of RAD50 sensitizes human tumor cells to cisplatin-based
chemotherapy. J. Clin. Invest. 119: 1974-1985, 2009. Note: Erratum:
J. Clin. Invest. 122: 4300 only, 2012.
2. 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.
3. Dolganov, G. M.; Maser, R. S.; Novikov, A.; Tosto, L.; Chong, S.;
Bressan, D. A.; Petrini, J. H. J.: Human Rad50 is physically associated
with human Mre11: identification of a conserved multiprotein complex
implicated in recombinational DNA repair. Molec. Cell Biol. 16:
4832-4841, 1996.
4. 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.
5. Hopfner, K.-P.; Craig, L.; Moncalian, G.; Zinkel, R. A.; Usui,
T.; Owen, B. A. L.; Karcher, A.; Henderson, B.; Bodmer, J.-L.; McMurray,
C. T.; Carney, J. P.; Petrini, J. H. J.; Tainer, J. A.: The Rad50
zinc-hook is a structure joining Mre11 complexes in DNA recombination
and repair. Nature 418: 562-566, 2002.
6. 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.
7. Luo, G.; Yao, M. S.; Bender, C. F.; Mills, M.; Bladl, A. R.; Bradley,
A.; Petrini, J. H. J.: Disruption of mRad50 causes embryonic stem
cell lethality, abnormal embryonic development, and sensitivity to
ionizing radiation. Proc. Nat. Acad. Sci. 96: 7376-7381, 1999.
8. 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.
9. Stracker, T. H.; Carson, C. T.; Weitzman, M. D.: Adenovirus oncoproteins
inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature 418:
348-352, 2002.
10. 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.
11. Waltes, R.; Kalb, R.; Gatei, M.; Kijas, A. W.; Stumm, M.; Sobeck,
A.; Wieland, B.; Varon, R.; Lerenthal, Y.; Lavin, M. F.; Schindler,
D.; Dork, T.: Human RAD50 deficiency in a Nijmegen breakage syndrome-like
disorder. Am. J. Hum. Genet. 84: 605-616, 2009.
12. 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.
13. 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.
14. 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.
15. 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: 11/20/2009
Ada Hamosh - updated: 10/6/2009
George E. Tiller - updated: 12/10/2008
Ada Hamosh - updated: 11/3/2005
George E. Tiller - updated: 12/4/2003
Ada Hamosh - updated: 10/1/2002
Ada Hamosh - updated: 7/24/2002
Stylianos E. Antonarakis - updated: 6/4/2001
Paul J. Converse - updated: 11/16/2000
Victor A. McKusick - updated: 6/27/2000
Ada Hamosh - updated: 7/30/1999
Victor A. McKusick - updated: 7/28/1999
*FIELD* CD
Rebekah S. Rasooly: 7/22/1999
*FIELD* ED
tpirozzi: 10/01/2013
wwang: 12/10/2009
ckniffin: 11/20/2009
alopez: 10/12/2009
terry: 10/6/2009
wwang: 12/10/2008
alopez: 11/7/2005
terry: 11/3/2005
alopez: 10/11/2005
terry: 10/10/2005
mgross: 4/14/2005
mgross: 12/4/2003
ckniffin: 3/11/2003
alopez: 11/14/2002
alopez: 10/2/2002
cwells: 10/1/2002
cwells: 7/26/2002
terry: 7/24/2002
mgross: 6/4/2001
joanna: 1/17/2001
mgross: 11/16/2000
alopez: 6/27/2000
carol: 6/27/2000
alopez: 7/30/1999
alopez: 7/28/1999
mgross: 7/22/1999
*RECORD*
*FIELD* NO
604040
*FIELD* TI
*604040 RAD50, S. CEREVISIAE, HOMOLOG OF; RAD50
*FIELD* TX
CLONING
The S. cerevisiae Rad50 gene encodes a protein that is essential for
read moredouble-stranded DNA break repair by nonhomologous DNA end joining and
chromosomal integration. The yeast Rad50, Mre11 (600814), and Xrs2
proteins appear to act in a multiprotein complex, consistent with the
observation that mutations in these genes confer nearly identical
phenotypes of no meiotic recombination and elevated rates of homologous
mitotic recombination. By direct selection of cDNAs from the 5q23-q31
chromosomal interval, Dolganov et al. (1996) isolated a cDNA encoding a
human Rad50 homolog. The human RAD50 gene spans 100 to 130 kb. Northern
blot analysis revealed that the RAD50 gene was expressed as a 5.5-kb
mRNA predominantly in testis. A faint 7-kb transcript, which the authors
considered to be an mRNA with an alternatively processed 3-prime end,
was also detected. Yeast Rad50 and the predicted 1,312-amino acid human
RAD50 protein share more than 50% identity in their N- and C-termini.
The central heptad repeat domains of the proteins have relatively
divergent primary sequences but are predicted to adopt very similar
coiled-coil structures. Using immunoprecipitation, Dolganov et al.
(1996) demonstrated that the 153-kD RAD50 is stably associated with
MRE11 in a protein complex, which may also include proteins of 95 kD,
200 kD, and 350 kD.
MAPPING
By inclusion within mapped clones and by analysis of somatic cell
hybrids, Dolganov et al. (1996) mapped the RAD50 gene to 5q31. They
suggested that a recombinational DNA repair deficiency may be associated
with the development of myeloid leukemia, since this chromosomal region
is frequently altered in acute myeloid leukemia and myelodysplastic
disease.
GENE FUNCTION
Trujillo et al. (1998) determined that the 95-kD protein in the
mammalian cell nuclear complex containing RAD50 and MRE11 is nibrin, or
p95 (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. They stated that
although p95 has little sequence homology to yeast Xrs2, the 2 proteins
can be considered functional analogs since they link the conserved
activities of MRE11/RAD50 to the cellular DNA damage response in their
respective organisms.
Zhong et al. (1999) showed that BRCA1 (113705) interacts in vitro and in
vivo 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.
Telomeres allow cells to distinguish natural chromosome ends from
damaged DNA and protect the ends from degradation and fusion. In human
cells, telomere protection depends on the TTAGGG repeat-binding factor,
TRF2 (602027), which may remodel telomeres into large duplex loops
(t-loops). Zhu et al. (2000) showed by nanoelectrospray tandem mass
spectrometry that RAD50 protein is present in TRF2 immunocomplexes.
Coimmunoprecipitation studies showed that a small fraction of RAD50,
MRE11, and p95 is associated with TRF2. Indirect immunofluorescence
demonstrated the presence of RAD50 and MRE11 at interphase telomeres.
NBS1 was associated with TRF2 and telomeres in S phase, but not in G1 or
G2. 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.
The MRE11/RAD50 protein complex functions in diverse aspects of the
cellular response to double strand breaks (DSBs), including the
detection of DNA damage, the activation of cell cycle checkpoints, and
DSB repair. Whereas genetic analyses in S. cerevisiae have provided
insight regarding DSB repair functions of this highly conserved complex,
the implication of the human complex in Nijmegen breakage syndrome
reveals its role in cell cycle checkpoint functions. Luo et al. (1999)
established mice with mutation in the mouse Rad50 gene and examined the
role of the Mre11/Rad50 protein complex in the DNA damage response.
Early embryonic cells deficient in Rad50 were hypersensitive to ionizing
radiation, consistent with a role for this complex in the repair of
ionizing radiation-induced DSBs. However, the null Rad50 mutation was
lethal in cultured embryonic stem cells and in early developing embryos,
indicating that the mammalian protein complex mediates functions in
normally growing cells that are essential for viability.
In mammalian cells, the conserved multiprotein MRN complex of MRE11,
RAD50, and NBS1 (602667) 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 concatamers too large to be packaged. Stracker et al. (2002)
investigated the cellular proteins involved in the concatamer formation
and how they are inactivated by E4 products during a wildtype infection.
They demonstrated that concatamerization 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
concatamerization. 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.
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.
Abuzeid et al. (2009) found that adenoviral-mediated transfection of a
mutant RAD50 gene into human squamous cell carcinoma cells disrupted the
MRN complex in a dominant-negative manner. The disruption significantly
downregulated MRN expression and enhanced the cytotoxicity of cisplatin
in vitro, with a corresponding increase in DNA damage and telomere
shortening. Treatment of nude mice with xenografts of
cisplatin-resistant human squamous cell cancer with this combination
therapy resulted in dramatic tumor regression with increased apoptosis
of tumor cells. The findings suggested that the use of targeted RAD50
disruption could be a chemosensitizing approach for cancer therapy in
the context of chemoresistance.
MOLECULAR GENETICS
In a patient with chromosome instability, x-ray hypersensitivity,
microcephaly, and growth retardation (Nijmegen breakage syndrome-like
disorder; 613078), Waltes et al. (2009) identified compound
heterozygosity in the RAD50 gene, for a nonsense mutation (604040.0001)
and a mutation at the natural stop codon leading to a 66-amino acid
extension (604040.0002). There was no detectable RNA or protein from the
allele carrying the nonsense mutation, whereas from the allele carrying
the extension mutation a small amount of RNA and protein could be
detected. Unlike patients with Nijmegen breakage syndrome (604391) and
MRE11 deficiency resulting in an ataxia-telangiectasia-like disorder
(604391), this patient with RAD50 deficiency did not have
immunodeficiency or malignancies. Cells from this patient were
intermediate in their radiosensitivity between wildtype and
ataxia-telangiectasia (208900) cells.
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.
Hopfner et al. (2002) presented a 2.2-angstrom crystal structure of the
Rad50 coiled-coil region that revealed an unexpected dimer interface at
the apex of the coiled coils in which pairs of conserved cys-x-x-cys
motifs form interlocking hooks that bind one zinc ion. Biochemical,
x-ray, and electron microscopy data indicated that these hooks can join
oppositely protruding Rad50 coiled-coil domains to form a flexible
bridge of up to 1,200 angstroms. This suggested a function for the long
insertion in the Rad50 ABC-ATPase. The Rad50 hook is functional, since
mutations in this motif confer radiation sensitivity in yeast and
disrupt binding at the distant Mre11 (600814) nuclease interface.
Hopfner et al. (2002) concluded that their data support an architectural
role for the Rad50 coiled coils in forming metal-mediated bridging
complexes between 2 DNA-binding heads. The resulting assemblies have
appropriate lengths and conformational properties to link sister
chromatids in homologous recombination and DNA ends in nonhomologous
end-joining.
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.
*FIELD* AV
.0001
NIJMEGEN BREAKAGE SYNDROME-LIKE DISORDER
RAD50, ARG1093TER
In a patient with Nijmegen breakage syndrome-like disorder (NBSLD;
613078), Waltes et al. (2009) identified compound heterozygosity for
mutations in the RAD50 gene. The maternal allele carried a C-to-T
transition at nucleotide 3277 in exon 21 of the RAD50 gene, resulting in
an arg-to-stop substitution at codon 1093 (R1093X). The paternal allele
carried a point mutation resulting in a 66-amino acid extension of the
protein (604040.0002). This mutation was associated with undetectable
RNA and protein and was not identified in 350 German chromosomes.
.0002
NIJMEGEN BREAKAGE SYNDROME-LIKE DISORDER
RAD50, TER1313TYR
In a patient with Nijmegen breakage syndrome-like disorder (NBSLD;
613078), Waltes et al. (2009) identified compound heterozygosity for
mutations in the RAD50 gene, for a nonsense mutation (604040.0001) and
an A-to-T transversion at nucleotide 3939, resulting in substitution of
the termination codon occurring at position 1313 with tyrosine at that
position and an extension of the reading frame by 66 amino acids
(X1313YextX*66). The prediction of a larger polypeptide produced by the
aberrant paternal allele was consistent with detection of a protein band
of increased molecular weight. Very low amounts of a larger polypeptide
detected by immunoblot analysis were considered a consequence either of
protein instability or unstable nonstop mRNA. This mutation was not
detected in 350 chromosomes from a German random population sample.
*FIELD* RF
1. Abuzeid, W. M.; Jiang, X.; Shi, G.; Wang, H.; Paulson, D.; Araki,
K.; Jungreis, D.; Carney, J.; O'Malley, B. W., Jr.; Li, D.: Molecular
disruption of RAD50 sensitizes human tumor cells to cisplatin-based
chemotherapy. J. Clin. Invest. 119: 1974-1985, 2009. Note: Erratum:
J. Clin. Invest. 122: 4300 only, 2012.
2. 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.
3. Dolganov, G. M.; Maser, R. S.; Novikov, A.; Tosto, L.; Chong, S.;
Bressan, D. A.; Petrini, J. H. J.: Human Rad50 is physically associated
with human Mre11: identification of a conserved multiprotein complex
implicated in recombinational DNA repair. Molec. Cell Biol. 16:
4832-4841, 1996.
4. 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.
5. Hopfner, K.-P.; Craig, L.; Moncalian, G.; Zinkel, R. A.; Usui,
T.; Owen, B. A. L.; Karcher, A.; Henderson, B.; Bodmer, J.-L.; McMurray,
C. T.; Carney, J. P.; Petrini, J. H. J.; Tainer, J. A.: The Rad50
zinc-hook is a structure joining Mre11 complexes in DNA recombination
and repair. Nature 418: 562-566, 2002.
6. 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.
7. Luo, G.; Yao, M. S.; Bender, C. F.; Mills, M.; Bladl, A. R.; Bradley,
A.; Petrini, J. H. J.: Disruption of mRad50 causes embryonic stem
cell lethality, abnormal embryonic development, and sensitivity to
ionizing radiation. Proc. Nat. Acad. Sci. 96: 7376-7381, 1999.
8. 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.
9. Stracker, T. H.; Carson, C. T.; Weitzman, M. D.: Adenovirus oncoproteins
inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature 418:
348-352, 2002.
10. 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.
11. Waltes, R.; Kalb, R.; Gatei, M.; Kijas, A. W.; Stumm, M.; Sobeck,
A.; Wieland, B.; Varon, R.; Lerenthal, Y.; Lavin, M. F.; Schindler,
D.; Dork, T.: Human RAD50 deficiency in a Nijmegen breakage syndrome-like
disorder. Am. J. Hum. Genet. 84: 605-616, 2009.
12. 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.
13. 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.
14. 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.
15. 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: 11/20/2009
Ada Hamosh - updated: 10/6/2009
George E. Tiller - updated: 12/10/2008
Ada Hamosh - updated: 11/3/2005
George E. Tiller - updated: 12/4/2003
Ada Hamosh - updated: 10/1/2002
Ada Hamosh - updated: 7/24/2002
Stylianos E. Antonarakis - updated: 6/4/2001
Paul J. Converse - updated: 11/16/2000
Victor A. McKusick - updated: 6/27/2000
Ada Hamosh - updated: 7/30/1999
Victor A. McKusick - updated: 7/28/1999
*FIELD* CD
Rebekah S. Rasooly: 7/22/1999
*FIELD* ED
tpirozzi: 10/01/2013
wwang: 12/10/2009
ckniffin: 11/20/2009
alopez: 10/12/2009
terry: 10/6/2009
wwang: 12/10/2008
alopez: 11/7/2005
terry: 11/3/2005
alopez: 10/11/2005
terry: 10/10/2005
mgross: 4/14/2005
mgross: 12/4/2003
ckniffin: 3/11/2003
alopez: 11/14/2002
alopez: 10/2/2002
cwells: 10/1/2002
cwells: 7/26/2002
terry: 7/24/2002
mgross: 6/4/2001
joanna: 1/17/2001
mgross: 11/16/2000
alopez: 6/27/2000
carol: 6/27/2000
alopez: 7/30/1999
alopez: 7/28/1999
mgross: 7/22/1999
MIM
613078
*RECORD*
*FIELD* NO
613078
*FIELD* TI
#613078 NIJMEGEN BREAKAGE SYNDROME-LIKE DISORDER; NBSLD
;;NBS-LIKE DISORDER;;
RAD50 DEFICIENCY;;
read moreMICROCEPHALY AND SPONTANEOUS CHROMOSOME INSTABILITY WITHOUT IMMUNODEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
phenotype results from mutation in the RAD50 gene (604040).
CLINICAL FEATURES
Barbi et al. (1991) reported a microcephalic, growth-retarded newborn
girl without major anomalies who had chromosome instability in
lymphocytes and fibroblasts. Frequent involvement of bands 7p13, 7q34,
14q11, and 14q32 suggested the diagnosis of ataxia-telangiectasia (AT;
208900). She had radioresistant DNA synthesis in fibroblasts and
radiation hypersensitivity of short-term lymphocyte cultures. Follow-up
at 4 years of age showed largely normal development and no signs of
telangiectasia, ataxia, or immunodeficiency. Serum AFP levels were
elevated at age 5 months, but declined to normal by age 2 years.
Fibroblasts showed radioresistant DNA synthesis typical of AT or the
Nijmegen breakage syndrome (251260).
Waltes et al. (2009) reported further phenotyping of this female, who
was 23 years of age at that time. She had mild to moderate retardation
of psychomoter development, mild spasticity, and very modestly impaired
sensomotor coordination manifesting as a slight and nonprogressive
ataxia. Physical exam showed a bird-like face and height, weight, and
head circumference well below the third percentile. Puberty and
secondary sexual characteristics appeared normal. She had areas of
hyper- and hypopigmentation diffusely and had severe hyperopia. She had
no history of infections, had normal immunoglobulin subclasses, and no
evidence of malignancy. By the age of 23 years, she was living in her
own apartment in an assisted living facility.
MOLECULAR GENETICS
In a patient with a Nijmegen breakage syndrome-like disorder (NBSLD),
Waltes et al. (2009) identified compound heterozygosity mutations in the
RAD50 gene, a maternally inherited nonsense mutation (604040.0001) and a
paternally inherited point mutation that resulted in extension of the
protein by 66 amino acids (604040.0002).
*FIELD* RF
1. Barbi, G.; Scheres, J. M. J. C.; Schindler, D.; Taalman, R. D.
F. M.; Rodens, K.; Mehnert, K.; Muller, M.; Seyschab, H.: Chromosome
instability and x-ray hypersensitivity in a microcephalic and growth-retarded
child. Am. J. Med. Genet. 40: 44-50, 1991.
2. Waltes, R.; Kalb, R.; Gatei, M.; Kijas, A. W.; Stumm, M.; Sobeck,
A.; Wieland, B.; Varon, R.; Lerenthal, Y.; Lavin, M. F.; Schindler,
D.; Dork, T.: Human RAD50 deficiency in a Nijmegen breakage syndrome-like
disorder. Am. J. Hum. Genet. 84: 605-616, 2009.
*FIELD* CD
Ada Hamosh: 10/12/2009
*FIELD* ED
alopez: 10/14/2009
alopez: 10/12/2009
*RECORD*
*FIELD* NO
613078
*FIELD* TI
#613078 NIJMEGEN BREAKAGE SYNDROME-LIKE DISORDER; NBSLD
;;NBS-LIKE DISORDER;;
RAD50 DEFICIENCY;;
read moreMICROCEPHALY AND SPONTANEOUS CHROMOSOME INSTABILITY WITHOUT IMMUNODEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
phenotype results from mutation in the RAD50 gene (604040).
CLINICAL FEATURES
Barbi et al. (1991) reported a microcephalic, growth-retarded newborn
girl without major anomalies who had chromosome instability in
lymphocytes and fibroblasts. Frequent involvement of bands 7p13, 7q34,
14q11, and 14q32 suggested the diagnosis of ataxia-telangiectasia (AT;
208900). She had radioresistant DNA synthesis in fibroblasts and
radiation hypersensitivity of short-term lymphocyte cultures. Follow-up
at 4 years of age showed largely normal development and no signs of
telangiectasia, ataxia, or immunodeficiency. Serum AFP levels were
elevated at age 5 months, but declined to normal by age 2 years.
Fibroblasts showed radioresistant DNA synthesis typical of AT or the
Nijmegen breakage syndrome (251260).
Waltes et al. (2009) reported further phenotyping of this female, who
was 23 years of age at that time. She had mild to moderate retardation
of psychomoter development, mild spasticity, and very modestly impaired
sensomotor coordination manifesting as a slight and nonprogressive
ataxia. Physical exam showed a bird-like face and height, weight, and
head circumference well below the third percentile. Puberty and
secondary sexual characteristics appeared normal. She had areas of
hyper- and hypopigmentation diffusely and had severe hyperopia. She had
no history of infections, had normal immunoglobulin subclasses, and no
evidence of malignancy. By the age of 23 years, she was living in her
own apartment in an assisted living facility.
MOLECULAR GENETICS
In a patient with a Nijmegen breakage syndrome-like disorder (NBSLD),
Waltes et al. (2009) identified compound heterozygosity mutations in the
RAD50 gene, a maternally inherited nonsense mutation (604040.0001) and a
paternally inherited point mutation that resulted in extension of the
protein by 66 amino acids (604040.0002).
*FIELD* RF
1. Barbi, G.; Scheres, J. M. J. C.; Schindler, D.; Taalman, R. D.
F. M.; Rodens, K.; Mehnert, K.; Muller, M.; Seyschab, H.: Chromosome
instability and x-ray hypersensitivity in a microcephalic and growth-retarded
child. Am. J. Med. Genet. 40: 44-50, 1991.
2. Waltes, R.; Kalb, R.; Gatei, M.; Kijas, A. W.; Stumm, M.; Sobeck,
A.; Wieland, B.; Varon, R.; Lerenthal, Y.; Lavin, M. F.; Schindler,
D.; Dork, T.: Human RAD50 deficiency in a Nijmegen breakage syndrome-like
disorder. Am. J. Hum. Genet. 84: 605-616, 2009.
*FIELD* CD
Ada Hamosh: 10/12/2009
*FIELD* ED
alopez: 10/14/2009
alopez: 10/12/2009