Full text data of CUL4A
CUL4A
[Confidence: low (only semi-automatic identification from reviews)]
Cullin-4A; CUL-4A
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Cullin-4A; CUL-4A
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q13619
ID CUL4A_HUMAN Reviewed; 759 AA.
AC Q13619; A2A2W2; O75834; Q589T6; Q5TC62; Q6UP08; Q9UP17;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-MAY-2006, sequence version 3.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Cullin-4A;
DE Short=CUL-4A;
GN Name=CUL4A;
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=9721878;
RA Chen L.-C., Manjeshwar S., Lu Y., Moore D., Ljung B.M., Kuo W.L.,
RA Dairkee S.H., Wernick M., Collins C., Smith H.S.;
RT "The human homologue for the Caenorhabditis elegans cul-4 gene is
RT amplified and overexpressed in primary breast cancers.";
RL Cancer Res. 58:3677-3683(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND INTERACTION WITH
RP CDT1.
RX PubMed=14578910; DOI=10.1038/ncb1061;
RA Higa L.A., Mihaylov I.S., Banks D.P., Zheng J., Zhang H.;
RT "Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes
RT constitutes a new checkpoint.";
RL Nat. Cell Biol. 5:1008-1015(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=15811626; DOI=10.1016/j.dnarep.2004.12.012;
RA Matsuda N., Azuma K., Saijo M., Iemura S., Hioki Y., Natsume T.,
RA Chiba T., Tanaka K., Tanaka K.;
RT "DDB2, the xeroderma pigmentosum group E gene product, is directly
RT ubiquitylated by Cullin 4A-based ubiquitin ligase complex.";
RL DNA Repair 4:537-545(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 236-759 (ISOFORMS 1/2), AND NEDDYLATION.
RX PubMed=9694792;
RA Osaka F., Kawasaki H., Aida N., Saeki M., Chiba T., Kawashima S.,
RA Tanaka K., Kato S.;
RT "A new NEDD8-ligating system for cullin-4A.";
RL Genes Dev. 12:2263-2268(1998).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 339-759 (ISOFORMS 1/2).
RX PubMed=8681378; DOI=10.1016/S0092-8674(00)81267-2;
RA Kipreos E.T., Lander L.E., Wing J.P., He W.W., Hedgecock E.M.;
RT "cul-1 is required for cell cycle exit in C. elegans and identifies a
RT novel gene family.";
RL Cell 85:829-839(1996).
RN [8]
RP NEDDYLATION.
RX PubMed=10597293; DOI=10.1038/sj.onc.1203093;
RA Hori T., Osaka F., Chiba T., Miyamoto C., Okabayashi K., Shimbara N.,
RA Kato S., Tanaka K.;
RT "Covalent modification of all members of human cullin family proteins
RT by NEDD8.";
RL Oncogene 18:6829-6834(1999).
RN [9]
RP INTERACTION WITH RBX1 AND RNF7.
RX PubMed=10230407; DOI=10.1016/S1097-2765(00)80482-7;
RA Ohta T., Michel J.J., Schottelius A.J., Xiong Y.;
RT "ROC1, a homolog of APC11, represents a family of cullin partners with
RT an associated ubiquitin ligase activity.";
RL Mol. Cell 3:535-541(1999).
RN [10]
RP IDENTIFICATION IN THE CSA COMPLEX WITH RBX1; DDB1 AND ERCC8, AND
RP INTERACTION OF THE CSA COMPLEX WITH RNA POLYMERASE II AND THE COP9
RP SIGNALOSOME.
RX PubMed=12732143; DOI=10.1016/S0092-8674(03)00316-7;
RA Groisman R., Polanowska J., Kuraoka I., Sawada J., Saijo M.,
RA Drapkin R., Kisselev A.F., Tanaka K., Nakatani Y.;
RT "The ubiquitin ligase activity in the DDB2 and CSA complexes is
RT differentially regulated by the COP9 signalosome in response to DNA
RT damage.";
RL Cell 113:357-367(2003).
RN [11]
RP INTERACTION WITH HOXA9, AND FUNCTION IN UBIQUITINATION OF HOXA9.
RX PubMed=14609952; DOI=10.1093/emboj/cdg577;
RA Zhang Y., Morrone G., Zhang J., Chen X., Lu X., Ma L., Moore M.,
RA Zhou P.;
RT "CUL-4A stimulates ubiquitylation and degradation of the HOXA9
RT homeodomain protein.";
RL EMBO J. 22:6057-6067(2003).
RN [12]
RP INTERACTION WITH TIP120A.
RX PubMed=12609982; DOI=10.1074/jbc.M213070200;
RA Min K.-W., Hwang J.-W., Lee J.-S., Park Y., Tamura T.-A., Yoon J.-B.;
RT "TIP120A associates with cullins and modulates ubiquitin ligase
RT activity.";
RL J. Biol. Chem. 278:15905-15910(2003).
RN [13]
RP INTERACTION WITH MDM2 AND TP53, AND FUNCTION IN UBIQUITINATION OF
RP TP53.
RX PubMed=15548678; DOI=10.1158/0008-5472.CAN-04-2598;
RA Nag A., Bagchi S., Raychaudhuri P.;
RT "Cul4A physically associates with MDM2 and participates in the
RT proteolysis of p53.";
RL Cancer Res. 64:8152-8155(2004).
RN [14]
RP INTERACTION WITH DDB1, AND FUNCTION IN CTD1 UBIQUITINATION.
RX PubMed=15448697; DOI=10.1038/ncb1172;
RA Hu J., McCall C.M., Ohta T., Xiong Y.;
RT "Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in
RT response to DNA damage.";
RL Nat. Cell Biol. 6:1003-1009(2004).
RN [15]
RP IDENTIFICATION IN THE DCX(DET1-COP1) COMPLEX WITH DDB1; RBX1; COP1 AND
RP DET1.
RX PubMed=14739464; DOI=10.1126/science.1093549;
RA Wertz I.E., O'Rourke K.M., Zhang Z., Dornan D., Arnott D.,
RA Deshaies R.J., Dixit V.M.;
RT "Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin
RT ligase.";
RL Science 303:1371-1374(2004).
RN [16]
RP INTERACTION WITH DDB1; DDB2 AND CAND1, AND MUTAGENESIS OF
RP 86-LEU--VAL-90 AND 139-TRP--HIS-142.
RX PubMed=16482215; DOI=10.1038/sj.emboj.7601002;
RA Nishitani H., Sugimoto N., Roukos V., Nakanishi Y., Saijo M.,
RA Obuse C., Tsurimoto T., Nakayama K.I., Nakayama K., Fujita M.,
RA Lygerou Z., Nishimoto T.;
RT "Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1
RT for proteolysis.";
RL EMBO J. 25:1126-1136(2006).
RN [17]
RP INTERACTION WITH VPRBP; DDB2; ERCC8; DCAF11; GRWD1; RFWD2; FBXW5;
RP RBBP7; GNB2; WSB1; WSB2; NUP43; PWP1; FBXW8; ATG16L1; KATNB1 AND
RP RBBP4, AND MUTAGENESIS OF 86-LEU--VAL-90 AND 139-TRP--HIS-142.
RX PubMed=17079684; DOI=10.1101/gad.1483206;
RA He Y.J., McCall C.M., Hu J., Zeng Y., Xiong Y.;
RT "DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-
RT ROC1 ubiquitin ligases.";
RL Genes Dev. 20:2949-2954(2006).
RN [18]
RP IDENTIFICATION IN COMPLEX WITH DDB1; DDB2 AND RBX1, MASS SPECTROMETRY,
RP AND FUNCTION.
RX PubMed=16678110; DOI=10.1016/j.molcel.2006.03.035;
RA Wang H., Zhai L., Xu J., Joo H.-Y., Jackson S., Erdjument-Bromage H.,
RA Tempst P., Xiong Y., Zhang Y.;
RT "Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin
RT ligase facilitates cellular response to DNA damage.";
RL Mol. Cell 22:383-394(2006).
RN [19]
RP INTERACTION WITH VPRBP; DTL; DDA1; DCAF6; DCAF4; DCAF16; DCAF17; DDB2;
RP DET1; WDTC1; DCAF5; DCAF11; WDR24A; RFWD2; PAFAH1B1 AND DCAF8.
RX PubMed=16949367; DOI=10.1016/j.molcel.2006.08.010;
RA Jin J., Arias E.E., Chen J., Harper J.W., Walter J.C.;
RT "A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2,
RT which is required for S phase destruction of the replication factor
RT Cdt1.";
RL Mol. Cell 23:709-721(2006).
RN [20]
RP INTERACTION WITH SKP2 AND CDKN1B, AND FUNCTION IN UBIQUITINATION OF
RP CDKN1B.
RX PubMed=16537899; DOI=10.1128/MCB.26.7.2531-2539.2006;
RA Bondar T., Kalinina A., Khair L., Kopanja D., Nag A., Bagchi S.,
RA Raychaudhuri P.;
RT "Cul4A and DDB1 associate with Skp2 to target p27Kip1 for proteolysis
RT involving the COP9 signalosome.";
RL Mol. Cell. Biol. 26:2531-2539(2006).
RN [21]
RP INTERACTION WITH DDB2; WDR26; RBBP5; RFWD2; WDR51B; SNRNP40; WDR61;
RP WDR76 AND WDR5.
RX PubMed=17041588; DOI=10.1038/ncb1490;
RA Higa L.A., Wu M., Ye T., Kobayashi R., Sun H., Zhang H.;
RT "CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat
RT proteins and regulates histone methylation.";
RL Nat. Cell Biol. 8:1277-1283(2006).
RN [22]
RP SELF-ASSOCIATION.
RX PubMed=17254749; DOI=10.1016/j.cellsig.2006.12.002;
RA Chew E.H., Poobalasingam T., Hawkey C.J., Hagen T.;
RT "Characterization of cullin-based E3 ubiquitin ligases in intact
RT mammalian cells -- evidence for cullin dimerization.";
RL Cell. Signal. 19:1071-1080(2007).
RN [23]
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 [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, AND MASS
RP 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 [25]
RP INTERACTION WITH EPSTEIN-BARR VIRUS BPLF1, AND DENEDDYLATION BY
RP EPSTEIN-BARR VIRUS BPLF1.
RX PubMed=20190741; DOI=10.1038/ncb2035;
RA Gastaldello S., Hildebrand S., Faridani O., Callegari S.,
RA Palmkvist M., Di Guglielmo C., Masucci M.G.;
RT "A deneddylase encoded by Epstein-Barr virus promotes viral DNA
RT replication by regulating the activity of cullin-RING ligases.";
RL Nat. Cell Biol. 12:351-361(2010).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, AND MASS
RP 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 [27]
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 [28]
RP INTERACTION WITH LRWD1.
RX PubMed=22935713; DOI=10.4161/cc.21870;
RA Shen Z., Prasanth S.G.;
RT "Orc2 protects ORCA from ubiquitin-mediated degradation.";
RL Cell Cycle 11:3578-3589(2012).
RN [29]
RP FUNCTION IN UBIQUITINATION OF H3.
RX PubMed=24209620; DOI=10.1016/j.cell.2013.10.014;
RA Han J., Zhang H., Zhang H., Wang Z., Zhou H., Zhang Z.;
RT "A Cul4 E3 ubiquitin ligase regulates histone hand-off during
RT nucleosome assembly.";
RL Cell 155:817-829(2013).
RN [30]
RP FUNCTION IN UBIQUITINATION OF DTL.
RX PubMed=23478445; DOI=10.1016/j.molcel.2013.02.003;
RA Abbas T., Mueller A.C., Shibata E., Keaton M., Rossi M., Dutta A.;
RT "CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and
RT regulates Pr-Set7/Set8-mediated cellular migration.";
RL Mol. Cell 49:1147-1158(2013).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) IN COMPLEX WITH DDB1; RBX1 AND
RP SV5-V.
RX PubMed=16964240; DOI=10.1038/nature05175;
RA Angers S., Li T., Yi X., MacCoss M.J., Moon R.T., Zheng N.;
RT "Molecular architecture and assembly of the DDB1-CUL4A ubiquitin
RT ligase machinery.";
RL Nature 443:590-593(2006).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (5.93 ANGSTROMS) OF 38-759 IN COMPLEX WITH DDB1;
RP RBX1 AND DDB2.
RX PubMed=22118460; DOI=10.1016/j.cell.2011.10.035;
RA Fischer E.S., Scrima A., Bohm K., Matsumoto S., Lingaraju G.M.,
RA Faty M., Yasuda T., Cavadini S., Wakasugi M., Hanaoka F., Iwai S.,
RA Gut H., Sugasawa K., Thoma N.H.;
RT "The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture,
RT targeting, and activation.";
RL Cell 147:1024-1039(2011).
CC -!- FUNCTION: Core component of multiple cullin-RING-based E3
CC ubiquitin-protein ligase complexes which mediate the
CC ubiquitination of target proteins. As a scaffold protein may
CC contribute to catalysis through positioning of the substrate and
CC the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase
CC activity of the complex is dependent on the neddylation of the
CC cullin subunit and is inhibited by the association of the
CC deneddylated cullin subunit with TIP120A/CAND1. The functional
CC specificity of the E3 ubiquitin-protein ligase complex depends on
CC the variable substrate recognition component. DCX(DET1-COP1)
CC directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of
CC XPC. DCX(DDB2) ubiquitinates histones H3-H4 and is required for
CC efficient histone deposition during replication-coupled (H3.1) and
CC replication-independent (H3.3) nucleosome assembly, probably by
CC facilitating the transfer of H3 from ASF1A/ASF1B to other
CC chaperones involved in histone deposition. DCX(DTL) plays a role
CC in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent
CC ubiquitination of TP53 in response to radiation-induced DNA damage
CC and during DNA replication. In association with DDB1 and SKP2
CC probably is involved in ubiquitination of CDKN1B/p27kip. Is
CC involved in ubiquitination of HOXA9. DCX(DTL) directs
CC autoubiquitination of DTL.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-
CC protein ligase complexes that seem to consist of DDB1, CUL4A or
CC CUL4B, RBX1 and a variable substrate recognition component which
CC seems to belong to a protein family described as DCAF (Ddb1- and
CC Cul4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat)
CC proteins. Component of the CSA complex (DCX(ERCC8) complex)
CC containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts
CC with RNA polymerase II; upon UV irradiation it interacts with the
CC COP9 signalosome and preferentially with the hyperphosphorylated
CC form of RNA polymerase II. Component of the DCX(DET1-COP1) complex
CC with the substrate recognition component DET1 and COP1. Component
CC of the DCX(DDB2) complex with the substrate recognition component
CC DDB2. Component of the DCX(DTL) complex with the putative
CC substrate recognition component DTL. Interacts with DDB1, RBX1,
CC RNF7, CTD1, TIP120A/CAND1, SKP2, CDKN1B, MDM2, TP53 and HOXA9.
CC Interacts with DDB2; the interactions with DDB2 and CAND1 are
CC mutually exclusive. Interacts with VPRBP, DTL, DDA1, DCAF6, DCAF4,
CC DCAF16, DCAF17, DET1, WDTC1, DCAF5, DCAF11, WDR24A, RFWD2,
CC PAFAH1B1, ERCC8, GRWD1, FBXW5, RBBP7, GNB2, WSB1, WSB2, NUP43,
CC PWP1, FBXW8, ATG16L1, KATNB1, RBBP4, RBBP5, LRWD1 and DCAF8. May
CC interact with WDR26, WDR51B, SNRNP40, WDR61, WDR76, WDR5. Can
CC self-associate. Interacts with Epstein-Barr virus BPLF1.
CC -!- INTERACTION:
CC Q86VP6:CAND1; NbExp=3; IntAct=EBI-456106, EBI-456077;
CC Q16531:DDB1; NbExp=4; IntAct=EBI-456106, EBI-350322;
CC Q92466:DDB2; NbExp=2; IntAct=EBI-456106, EBI-1176171;
CC Q15291:RBBP5; NbExp=3; IntAct=EBI-456106, EBI-592823;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q13619-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13619-2; Sequence=VSP_018577;
CC -!- PTM: Neddylated. Deneddylated via its interaction with the COP9
CC signalosome (CSN) complex (By similarity). Deneddylated by
CC Epstein-Barr virus BPLF1 leading to a S-phase-like environment
CC that is required for efficient replication of the viral genome.
CC -!- SIMILARITY: Belongs to the cullin family.
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DR EMBL; AF077188; AAD45191.1; -; mRNA.
DR EMBL; AY365124; AAR13072.1; -; mRNA.
DR EMBL; AB178950; BAD93235.1; -; mRNA.
DR EMBL; AL136221; CAM18410.1; -; Genomic_DNA.
DR EMBL; AL136221; CAI13795.1; -; Genomic_DNA.
DR EMBL; BC008308; AAH08308.2; -; mRNA.
DR EMBL; AB012193; BAA33146.1; -; mRNA.
DR EMBL; U58090; AAC50547.1; -; mRNA.
DR RefSeq; NP_001008895.1; NM_001008895.2.
DR RefSeq; NP_001265442.1; NM_001278513.1.
DR RefSeq; NP_003580.1; NM_003589.2.
DR UniGene; Hs.339735; -.
DR PDB; 2HYE; X-ray; 3.10 A; C=1-759.
DR PDB; 4A0K; X-ray; 5.93 A; A=35-759.
DR PDBsum; 2HYE; -.
DR PDBsum; 4A0K; -.
DR ProteinModelPortal; Q13619; -.
DR SMR; Q13619; 41-759.
DR DIP; DIP-31610N; -.
DR IntAct; Q13619; 34.
DR MINT; MINT-4532640; -.
DR STRING; 9606.ENSP00000364589; -.
DR PhosphoSite; Q13619; -.
DR DMDM; 108936013; -.
DR PaxDb; Q13619; -.
DR PRIDE; Q13619; -.
DR DNASU; 8451; -.
DR Ensembl; ENST00000326335; ENSP00000322132; ENSG00000139842.
DR Ensembl; ENST00000375440; ENSP00000364589; ENSG00000139842.
DR Ensembl; ENST00000375441; ENSP00000364590; ENSG00000139842.
DR Ensembl; ENST00000451881; ENSP00000389118; ENSG00000139842.
DR GeneID; 8451; -.
DR KEGG; hsa:8451; -.
DR UCSC; uc010agu.3; human.
DR CTD; 8451; -.
DR GeneCards; GC13P113863; -.
DR HGNC; HGNC:2554; CUL4A.
DR MIM; 603137; gene.
DR neXtProt; NX_Q13619; -.
DR PharmGKB; PA27050; -.
DR eggNOG; COG5647; -.
DR HOVERGEN; HBG003619; -.
DR InParanoid; Q13619; -.
DR KO; K10609; -.
DR OMA; HVVEVCF; -.
DR OrthoDB; EOG75TMB5; -.
DR UniPathway; UPA00143; -.
DR EvolutionaryTrace; Q13619; -.
DR GeneWiki; CUL4A; -.
DR GenomeRNAi; 8451; -.
DR NextBio; 31624; -.
DR PRO; PR:Q13619; -.
DR ArrayExpress; Q13619; -.
DR Bgee; Q13619; -.
DR CleanEx; HS_CUL4A; -.
DR Genevestigator; Q13619; -.
DR GO; GO:0031464; C:Cul4A-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0007050; P:cell cycle arrest; TAS:ProtInc.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:ProtInc.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0008285; P:negative regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR GO; GO:0007346; P:regulation of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0051246; P:regulation of protein metabolic process; IEA:Ensembl.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 1.10.10.10; -; 2.
DR InterPro; IPR016157; Cullin_CS.
DR InterPro; IPR016158; Cullin_homology.
DR InterPro; IPR001373; Cullin_N.
DR InterPro; IPR019559; Cullin_neddylation_domain.
DR InterPro; IPR016159; Cullin_repeat-like_dom.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00888; Cullin; 1.
DR Pfam; PF10557; Cullin_Nedd8; 1.
DR SMART; SM00182; CULLIN; 1.
DR SMART; SM00884; Cullin_Nedd8; 1.
DR SUPFAM; SSF74788; SSF74788; 1.
DR SUPFAM; SSF75632; SSF75632; 1.
DR PROSITE; PS01256; CULLIN_1; 1.
DR PROSITE; PS50069; CULLIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; DNA damage;
KW DNA repair; Host-virus interaction; Isopeptide bond; Phosphoprotein;
KW Polymorphism; Reference proteome; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1 759 Cullin-4A.
FT /FTId=PRO_0000119795.
FT MOD_RES 10 10 Phosphoserine.
FT CROSSLNK 33 33 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 705 705 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in NEDD8) (By
FT similarity).
FT VAR_SEQ 1 100 Missing (in isoform 2).
FT /FTId=VSP_018577.
FT VARIANT 644 644 K -> R (in dbSNP:rs2302757).
FT /FTId=VAR_020341.
FT MUTAGEN 86 90 LYQAV->AAAAA: Largely reduces interaction
FT with DDB1; abolishes interaction with
FT DDB2.
FT MUTAGEN 139 142 WQDH->AADA: Largely reduces interaction
FT with DDB1; abolishes interaction with
FT DDB2.
FT CONFLICT 281 281 S -> T (in Ref. 3; BAD93235).
FT CONFLICT 339 346 HWSEYIKT -> NSARARAA (in Ref. 7;
FT AAC50547).
FT CONFLICT 496 496 K -> R (in Ref. 3; BAD93235).
FT TURN 58 61
FT HELIX 62 71
FT HELIX 83 93
FT TURN 96 98
FT HELIX 99 121
FT HELIX 130 152
FT HELIX 154 157
FT TURN 158 162
FT STRAND 165 167
FT HELIX 170 180
FT TURN 181 183
FT STRAND 184 186
FT HELIX 189 191
FT HELIX 193 201
FT TURN 202 206
FT HELIX 211 223
FT TURN 227 231
FT HELIX 232 253
FT HELIX 256 269
FT HELIX 271 274
FT TURN 275 277
FT TURN 280 282
FT HELIX 283 294
FT TURN 295 297
FT HELIX 300 304
FT HELIX 307 311
FT TURN 312 314
FT HELIX 316 328
FT HELIX 332 352
FT HELIX 355 357
FT TURN 358 360
FT HELIX 361 377
FT TURN 378 382
FT HELIX 384 398
FT HELIX 404 417
FT HELIX 421 423
FT HELIX 429 440
FT HELIX 446 462
FT HELIX 469 480
FT TURN 481 483
FT TURN 485 488
FT HELIX 489 513
FT STRAND 522 529
FT TURN 530 532
FT HELIX 545 559
FT STRAND 564 566
FT HELIX 571 573
FT STRAND 575 579
FT STRAND 588 592
FT HELIX 593 601
FT HELIX 610 616
FT HELIX 621 629
FT TURN 630 636
FT STRAND 638 641
FT STRAND 645 647
FT STRAND 653 656
FT STRAND 665 668
FT HELIX 670 674
FT HELIX 678 706
FT STRAND 707 711
FT HELIX 713 722
FT STRAND 723 725
FT HELIX 729 741
FT STRAND 754 756
SQ SEQUENCE 759 AA; 87680 MW; 3C4C6A1BBD94D51B CRC64;
MADEAPRKGS FSALVGRTNG LTKPAALAAA PAKPGGAGGS KKLVIKNFRD RPRLPDNYTQ
DTWRKLHEAV RAVQSSTSIR YNLEELYQAV ENLCSHKVSP MLYKQLRQAC EDHVQAQILP
FREDSLDSVL FLKKINTCWQ DHCRQMIMIR SIFLFLDRTY VLQNSTLPSI WDMGLELFRT
HIISDKMVQS KTIDGILLLI ERERSGEAVD RSLLRSLLGM LSDLQVYKDS FELKFLEETN
CLYAAEGQRL MQEREVPEYL NHVSKRLEEE GDRVITYLDH STQKPLIACV EKQLLGEHLT
AILQKGLDHL LDENRVPDLA QMYQLFSRVR GGQQALLQHW SEYIKTFGTA IVINPEKDKD
MVQDLLDFKD KVDHVIEVCF QKNERFVNLM KESFETFINK RPNKPAELIA KHVDSKLRAG
NKEATDEELE RTLDKIMILF RFIHGKDVFE AFYKKDLAKR LLVGKSASVD AEKSMLSKLK
HECGAAFTSK LEGMFKDMEL SKDIMVHFKQ HMQNQSDSGP IDLTVNILTM GYWPTYTPME
VHLTPEMIKL QEVFKAFYLG KHSGRKLQWQ TTLGHAVLKA EFKEGKKEFQ VSLFQTLVLL
MFNEGDGFSF EEIKMATGIE DSELRRTLQS LACGKARVLI KSPKGKEVED GDKFIFNGEF
KHKLFRIKIN QIQMKETVEE QVSTTERVFQ DRQYQIDAAI VRIMKMRKTL GHNLLVSELY
NQLKFPVKPG DLKKRIESLI DRDYMERDKD NPNQYHYVA
//
ID CUL4A_HUMAN Reviewed; 759 AA.
AC Q13619; A2A2W2; O75834; Q589T6; Q5TC62; Q6UP08; Q9UP17;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-MAY-2006, sequence version 3.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Cullin-4A;
DE Short=CUL-4A;
GN Name=CUL4A;
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=9721878;
RA Chen L.-C., Manjeshwar S., Lu Y., Moore D., Ljung B.M., Kuo W.L.,
RA Dairkee S.H., Wernick M., Collins C., Smith H.S.;
RT "The human homologue for the Caenorhabditis elegans cul-4 gene is
RT amplified and overexpressed in primary breast cancers.";
RL Cancer Res. 58:3677-3683(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND INTERACTION WITH
RP CDT1.
RX PubMed=14578910; DOI=10.1038/ncb1061;
RA Higa L.A., Mihaylov I.S., Banks D.P., Zheng J., Zhang H.;
RT "Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes
RT constitutes a new checkpoint.";
RL Nat. Cell Biol. 5:1008-1015(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=15811626; DOI=10.1016/j.dnarep.2004.12.012;
RA Matsuda N., Azuma K., Saijo M., Iemura S., Hioki Y., Natsume T.,
RA Chiba T., Tanaka K., Tanaka K.;
RT "DDB2, the xeroderma pigmentosum group E gene product, is directly
RT ubiquitylated by Cullin 4A-based ubiquitin ligase complex.";
RL DNA Repair 4:537-545(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 236-759 (ISOFORMS 1/2), AND NEDDYLATION.
RX PubMed=9694792;
RA Osaka F., Kawasaki H., Aida N., Saeki M., Chiba T., Kawashima S.,
RA Tanaka K., Kato S.;
RT "A new NEDD8-ligating system for cullin-4A.";
RL Genes Dev. 12:2263-2268(1998).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 339-759 (ISOFORMS 1/2).
RX PubMed=8681378; DOI=10.1016/S0092-8674(00)81267-2;
RA Kipreos E.T., Lander L.E., Wing J.P., He W.W., Hedgecock E.M.;
RT "cul-1 is required for cell cycle exit in C. elegans and identifies a
RT novel gene family.";
RL Cell 85:829-839(1996).
RN [8]
RP NEDDYLATION.
RX PubMed=10597293; DOI=10.1038/sj.onc.1203093;
RA Hori T., Osaka F., Chiba T., Miyamoto C., Okabayashi K., Shimbara N.,
RA Kato S., Tanaka K.;
RT "Covalent modification of all members of human cullin family proteins
RT by NEDD8.";
RL Oncogene 18:6829-6834(1999).
RN [9]
RP INTERACTION WITH RBX1 AND RNF7.
RX PubMed=10230407; DOI=10.1016/S1097-2765(00)80482-7;
RA Ohta T., Michel J.J., Schottelius A.J., Xiong Y.;
RT "ROC1, a homolog of APC11, represents a family of cullin partners with
RT an associated ubiquitin ligase activity.";
RL Mol. Cell 3:535-541(1999).
RN [10]
RP IDENTIFICATION IN THE CSA COMPLEX WITH RBX1; DDB1 AND ERCC8, AND
RP INTERACTION OF THE CSA COMPLEX WITH RNA POLYMERASE II AND THE COP9
RP SIGNALOSOME.
RX PubMed=12732143; DOI=10.1016/S0092-8674(03)00316-7;
RA Groisman R., Polanowska J., Kuraoka I., Sawada J., Saijo M.,
RA Drapkin R., Kisselev A.F., Tanaka K., Nakatani Y.;
RT "The ubiquitin ligase activity in the DDB2 and CSA complexes is
RT differentially regulated by the COP9 signalosome in response to DNA
RT damage.";
RL Cell 113:357-367(2003).
RN [11]
RP INTERACTION WITH HOXA9, AND FUNCTION IN UBIQUITINATION OF HOXA9.
RX PubMed=14609952; DOI=10.1093/emboj/cdg577;
RA Zhang Y., Morrone G., Zhang J., Chen X., Lu X., Ma L., Moore M.,
RA Zhou P.;
RT "CUL-4A stimulates ubiquitylation and degradation of the HOXA9
RT homeodomain protein.";
RL EMBO J. 22:6057-6067(2003).
RN [12]
RP INTERACTION WITH TIP120A.
RX PubMed=12609982; DOI=10.1074/jbc.M213070200;
RA Min K.-W., Hwang J.-W., Lee J.-S., Park Y., Tamura T.-A., Yoon J.-B.;
RT "TIP120A associates with cullins and modulates ubiquitin ligase
RT activity.";
RL J. Biol. Chem. 278:15905-15910(2003).
RN [13]
RP INTERACTION WITH MDM2 AND TP53, AND FUNCTION IN UBIQUITINATION OF
RP TP53.
RX PubMed=15548678; DOI=10.1158/0008-5472.CAN-04-2598;
RA Nag A., Bagchi S., Raychaudhuri P.;
RT "Cul4A physically associates with MDM2 and participates in the
RT proteolysis of p53.";
RL Cancer Res. 64:8152-8155(2004).
RN [14]
RP INTERACTION WITH DDB1, AND FUNCTION IN CTD1 UBIQUITINATION.
RX PubMed=15448697; DOI=10.1038/ncb1172;
RA Hu J., McCall C.M., Ohta T., Xiong Y.;
RT "Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in
RT response to DNA damage.";
RL Nat. Cell Biol. 6:1003-1009(2004).
RN [15]
RP IDENTIFICATION IN THE DCX(DET1-COP1) COMPLEX WITH DDB1; RBX1; COP1 AND
RP DET1.
RX PubMed=14739464; DOI=10.1126/science.1093549;
RA Wertz I.E., O'Rourke K.M., Zhang Z., Dornan D., Arnott D.,
RA Deshaies R.J., Dixit V.M.;
RT "Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin
RT ligase.";
RL Science 303:1371-1374(2004).
RN [16]
RP INTERACTION WITH DDB1; DDB2 AND CAND1, AND MUTAGENESIS OF
RP 86-LEU--VAL-90 AND 139-TRP--HIS-142.
RX PubMed=16482215; DOI=10.1038/sj.emboj.7601002;
RA Nishitani H., Sugimoto N., Roukos V., Nakanishi Y., Saijo M.,
RA Obuse C., Tsurimoto T., Nakayama K.I., Nakayama K., Fujita M.,
RA Lygerou Z., Nishimoto T.;
RT "Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1
RT for proteolysis.";
RL EMBO J. 25:1126-1136(2006).
RN [17]
RP INTERACTION WITH VPRBP; DDB2; ERCC8; DCAF11; GRWD1; RFWD2; FBXW5;
RP RBBP7; GNB2; WSB1; WSB2; NUP43; PWP1; FBXW8; ATG16L1; KATNB1 AND
RP RBBP4, AND MUTAGENESIS OF 86-LEU--VAL-90 AND 139-TRP--HIS-142.
RX PubMed=17079684; DOI=10.1101/gad.1483206;
RA He Y.J., McCall C.M., Hu J., Zeng Y., Xiong Y.;
RT "DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-
RT ROC1 ubiquitin ligases.";
RL Genes Dev. 20:2949-2954(2006).
RN [18]
RP IDENTIFICATION IN COMPLEX WITH DDB1; DDB2 AND RBX1, MASS SPECTROMETRY,
RP AND FUNCTION.
RX PubMed=16678110; DOI=10.1016/j.molcel.2006.03.035;
RA Wang H., Zhai L., Xu J., Joo H.-Y., Jackson S., Erdjument-Bromage H.,
RA Tempst P., Xiong Y., Zhang Y.;
RT "Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin
RT ligase facilitates cellular response to DNA damage.";
RL Mol. Cell 22:383-394(2006).
RN [19]
RP INTERACTION WITH VPRBP; DTL; DDA1; DCAF6; DCAF4; DCAF16; DCAF17; DDB2;
RP DET1; WDTC1; DCAF5; DCAF11; WDR24A; RFWD2; PAFAH1B1 AND DCAF8.
RX PubMed=16949367; DOI=10.1016/j.molcel.2006.08.010;
RA Jin J., Arias E.E., Chen J., Harper J.W., Walter J.C.;
RT "A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2,
RT which is required for S phase destruction of the replication factor
RT Cdt1.";
RL Mol. Cell 23:709-721(2006).
RN [20]
RP INTERACTION WITH SKP2 AND CDKN1B, AND FUNCTION IN UBIQUITINATION OF
RP CDKN1B.
RX PubMed=16537899; DOI=10.1128/MCB.26.7.2531-2539.2006;
RA Bondar T., Kalinina A., Khair L., Kopanja D., Nag A., Bagchi S.,
RA Raychaudhuri P.;
RT "Cul4A and DDB1 associate with Skp2 to target p27Kip1 for proteolysis
RT involving the COP9 signalosome.";
RL Mol. Cell. Biol. 26:2531-2539(2006).
RN [21]
RP INTERACTION WITH DDB2; WDR26; RBBP5; RFWD2; WDR51B; SNRNP40; WDR61;
RP WDR76 AND WDR5.
RX PubMed=17041588; DOI=10.1038/ncb1490;
RA Higa L.A., Wu M., Ye T., Kobayashi R., Sun H., Zhang H.;
RT "CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat
RT proteins and regulates histone methylation.";
RL Nat. Cell Biol. 8:1277-1283(2006).
RN [22]
RP SELF-ASSOCIATION.
RX PubMed=17254749; DOI=10.1016/j.cellsig.2006.12.002;
RA Chew E.H., Poobalasingam T., Hawkey C.J., Hagen T.;
RT "Characterization of cullin-based E3 ubiquitin ligases in intact
RT mammalian cells -- evidence for cullin dimerization.";
RL Cell. Signal. 19:1071-1080(2007).
RN [23]
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 [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, AND MASS
RP 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 [25]
RP INTERACTION WITH EPSTEIN-BARR VIRUS BPLF1, AND DENEDDYLATION BY
RP EPSTEIN-BARR VIRUS BPLF1.
RX PubMed=20190741; DOI=10.1038/ncb2035;
RA Gastaldello S., Hildebrand S., Faridani O., Callegari S.,
RA Palmkvist M., Di Guglielmo C., Masucci M.G.;
RT "A deneddylase encoded by Epstein-Barr virus promotes viral DNA
RT replication by regulating the activity of cullin-RING ligases.";
RL Nat. Cell Biol. 12:351-361(2010).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, AND MASS
RP 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 [27]
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 [28]
RP INTERACTION WITH LRWD1.
RX PubMed=22935713; DOI=10.4161/cc.21870;
RA Shen Z., Prasanth S.G.;
RT "Orc2 protects ORCA from ubiquitin-mediated degradation.";
RL Cell Cycle 11:3578-3589(2012).
RN [29]
RP FUNCTION IN UBIQUITINATION OF H3.
RX PubMed=24209620; DOI=10.1016/j.cell.2013.10.014;
RA Han J., Zhang H., Zhang H., Wang Z., Zhou H., Zhang Z.;
RT "A Cul4 E3 ubiquitin ligase regulates histone hand-off during
RT nucleosome assembly.";
RL Cell 155:817-829(2013).
RN [30]
RP FUNCTION IN UBIQUITINATION OF DTL.
RX PubMed=23478445; DOI=10.1016/j.molcel.2013.02.003;
RA Abbas T., Mueller A.C., Shibata E., Keaton M., Rossi M., Dutta A.;
RT "CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and
RT regulates Pr-Set7/Set8-mediated cellular migration.";
RL Mol. Cell 49:1147-1158(2013).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) IN COMPLEX WITH DDB1; RBX1 AND
RP SV5-V.
RX PubMed=16964240; DOI=10.1038/nature05175;
RA Angers S., Li T., Yi X., MacCoss M.J., Moon R.T., Zheng N.;
RT "Molecular architecture and assembly of the DDB1-CUL4A ubiquitin
RT ligase machinery.";
RL Nature 443:590-593(2006).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (5.93 ANGSTROMS) OF 38-759 IN COMPLEX WITH DDB1;
RP RBX1 AND DDB2.
RX PubMed=22118460; DOI=10.1016/j.cell.2011.10.035;
RA Fischer E.S., Scrima A., Bohm K., Matsumoto S., Lingaraju G.M.,
RA Faty M., Yasuda T., Cavadini S., Wakasugi M., Hanaoka F., Iwai S.,
RA Gut H., Sugasawa K., Thoma N.H.;
RT "The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture,
RT targeting, and activation.";
RL Cell 147:1024-1039(2011).
CC -!- FUNCTION: Core component of multiple cullin-RING-based E3
CC ubiquitin-protein ligase complexes which mediate the
CC ubiquitination of target proteins. As a scaffold protein may
CC contribute to catalysis through positioning of the substrate and
CC the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase
CC activity of the complex is dependent on the neddylation of the
CC cullin subunit and is inhibited by the association of the
CC deneddylated cullin subunit with TIP120A/CAND1. The functional
CC specificity of the E3 ubiquitin-protein ligase complex depends on
CC the variable substrate recognition component. DCX(DET1-COP1)
CC directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of
CC XPC. DCX(DDB2) ubiquitinates histones H3-H4 and is required for
CC efficient histone deposition during replication-coupled (H3.1) and
CC replication-independent (H3.3) nucleosome assembly, probably by
CC facilitating the transfer of H3 from ASF1A/ASF1B to other
CC chaperones involved in histone deposition. DCX(DTL) plays a role
CC in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent
CC ubiquitination of TP53 in response to radiation-induced DNA damage
CC and during DNA replication. In association with DDB1 and SKP2
CC probably is involved in ubiquitination of CDKN1B/p27kip. Is
CC involved in ubiquitination of HOXA9. DCX(DTL) directs
CC autoubiquitination of DTL.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-
CC protein ligase complexes that seem to consist of DDB1, CUL4A or
CC CUL4B, RBX1 and a variable substrate recognition component which
CC seems to belong to a protein family described as DCAF (Ddb1- and
CC Cul4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat)
CC proteins. Component of the CSA complex (DCX(ERCC8) complex)
CC containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts
CC with RNA polymerase II; upon UV irradiation it interacts with the
CC COP9 signalosome and preferentially with the hyperphosphorylated
CC form of RNA polymerase II. Component of the DCX(DET1-COP1) complex
CC with the substrate recognition component DET1 and COP1. Component
CC of the DCX(DDB2) complex with the substrate recognition component
CC DDB2. Component of the DCX(DTL) complex with the putative
CC substrate recognition component DTL. Interacts with DDB1, RBX1,
CC RNF7, CTD1, TIP120A/CAND1, SKP2, CDKN1B, MDM2, TP53 and HOXA9.
CC Interacts with DDB2; the interactions with DDB2 and CAND1 are
CC mutually exclusive. Interacts with VPRBP, DTL, DDA1, DCAF6, DCAF4,
CC DCAF16, DCAF17, DET1, WDTC1, DCAF5, DCAF11, WDR24A, RFWD2,
CC PAFAH1B1, ERCC8, GRWD1, FBXW5, RBBP7, GNB2, WSB1, WSB2, NUP43,
CC PWP1, FBXW8, ATG16L1, KATNB1, RBBP4, RBBP5, LRWD1 and DCAF8. May
CC interact with WDR26, WDR51B, SNRNP40, WDR61, WDR76, WDR5. Can
CC self-associate. Interacts with Epstein-Barr virus BPLF1.
CC -!- INTERACTION:
CC Q86VP6:CAND1; NbExp=3; IntAct=EBI-456106, EBI-456077;
CC Q16531:DDB1; NbExp=4; IntAct=EBI-456106, EBI-350322;
CC Q92466:DDB2; NbExp=2; IntAct=EBI-456106, EBI-1176171;
CC Q15291:RBBP5; NbExp=3; IntAct=EBI-456106, EBI-592823;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q13619-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13619-2; Sequence=VSP_018577;
CC -!- PTM: Neddylated. Deneddylated via its interaction with the COP9
CC signalosome (CSN) complex (By similarity). Deneddylated by
CC Epstein-Barr virus BPLF1 leading to a S-phase-like environment
CC that is required for efficient replication of the viral genome.
CC -!- SIMILARITY: Belongs to the cullin family.
CC -----------------------------------------------------------------------
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DR EMBL; AF077188; AAD45191.1; -; mRNA.
DR EMBL; AY365124; AAR13072.1; -; mRNA.
DR EMBL; AB178950; BAD93235.1; -; mRNA.
DR EMBL; AL136221; CAM18410.1; -; Genomic_DNA.
DR EMBL; AL136221; CAI13795.1; -; Genomic_DNA.
DR EMBL; BC008308; AAH08308.2; -; mRNA.
DR EMBL; AB012193; BAA33146.1; -; mRNA.
DR EMBL; U58090; AAC50547.1; -; mRNA.
DR RefSeq; NP_001008895.1; NM_001008895.2.
DR RefSeq; NP_001265442.1; NM_001278513.1.
DR RefSeq; NP_003580.1; NM_003589.2.
DR UniGene; Hs.339735; -.
DR PDB; 2HYE; X-ray; 3.10 A; C=1-759.
DR PDB; 4A0K; X-ray; 5.93 A; A=35-759.
DR PDBsum; 2HYE; -.
DR PDBsum; 4A0K; -.
DR ProteinModelPortal; Q13619; -.
DR SMR; Q13619; 41-759.
DR DIP; DIP-31610N; -.
DR IntAct; Q13619; 34.
DR MINT; MINT-4532640; -.
DR STRING; 9606.ENSP00000364589; -.
DR PhosphoSite; Q13619; -.
DR DMDM; 108936013; -.
DR PaxDb; Q13619; -.
DR PRIDE; Q13619; -.
DR DNASU; 8451; -.
DR Ensembl; ENST00000326335; ENSP00000322132; ENSG00000139842.
DR Ensembl; ENST00000375440; ENSP00000364589; ENSG00000139842.
DR Ensembl; ENST00000375441; ENSP00000364590; ENSG00000139842.
DR Ensembl; ENST00000451881; ENSP00000389118; ENSG00000139842.
DR GeneID; 8451; -.
DR KEGG; hsa:8451; -.
DR UCSC; uc010agu.3; human.
DR CTD; 8451; -.
DR GeneCards; GC13P113863; -.
DR HGNC; HGNC:2554; CUL4A.
DR MIM; 603137; gene.
DR neXtProt; NX_Q13619; -.
DR PharmGKB; PA27050; -.
DR eggNOG; COG5647; -.
DR HOVERGEN; HBG003619; -.
DR InParanoid; Q13619; -.
DR KO; K10609; -.
DR OMA; HVVEVCF; -.
DR OrthoDB; EOG75TMB5; -.
DR UniPathway; UPA00143; -.
DR EvolutionaryTrace; Q13619; -.
DR GeneWiki; CUL4A; -.
DR GenomeRNAi; 8451; -.
DR NextBio; 31624; -.
DR PRO; PR:Q13619; -.
DR ArrayExpress; Q13619; -.
DR Bgee; Q13619; -.
DR CleanEx; HS_CUL4A; -.
DR Genevestigator; Q13619; -.
DR GO; GO:0031464; C:Cul4A-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0007050; P:cell cycle arrest; TAS:ProtInc.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:ProtInc.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0008285; P:negative regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR GO; GO:0007346; P:regulation of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0051246; P:regulation of protein metabolic process; IEA:Ensembl.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 1.10.10.10; -; 2.
DR InterPro; IPR016157; Cullin_CS.
DR InterPro; IPR016158; Cullin_homology.
DR InterPro; IPR001373; Cullin_N.
DR InterPro; IPR019559; Cullin_neddylation_domain.
DR InterPro; IPR016159; Cullin_repeat-like_dom.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00888; Cullin; 1.
DR Pfam; PF10557; Cullin_Nedd8; 1.
DR SMART; SM00182; CULLIN; 1.
DR SMART; SM00884; Cullin_Nedd8; 1.
DR SUPFAM; SSF74788; SSF74788; 1.
DR SUPFAM; SSF75632; SSF75632; 1.
DR PROSITE; PS01256; CULLIN_1; 1.
DR PROSITE; PS50069; CULLIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; DNA damage;
KW DNA repair; Host-virus interaction; Isopeptide bond; Phosphoprotein;
KW Polymorphism; Reference proteome; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1 759 Cullin-4A.
FT /FTId=PRO_0000119795.
FT MOD_RES 10 10 Phosphoserine.
FT CROSSLNK 33 33 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT CROSSLNK 705 705 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in NEDD8) (By
FT similarity).
FT VAR_SEQ 1 100 Missing (in isoform 2).
FT /FTId=VSP_018577.
FT VARIANT 644 644 K -> R (in dbSNP:rs2302757).
FT /FTId=VAR_020341.
FT MUTAGEN 86 90 LYQAV->AAAAA: Largely reduces interaction
FT with DDB1; abolishes interaction with
FT DDB2.
FT MUTAGEN 139 142 WQDH->AADA: Largely reduces interaction
FT with DDB1; abolishes interaction with
FT DDB2.
FT CONFLICT 281 281 S -> T (in Ref. 3; BAD93235).
FT CONFLICT 339 346 HWSEYIKT -> NSARARAA (in Ref. 7;
FT AAC50547).
FT CONFLICT 496 496 K -> R (in Ref. 3; BAD93235).
FT TURN 58 61
FT HELIX 62 71
FT HELIX 83 93
FT TURN 96 98
FT HELIX 99 121
FT HELIX 130 152
FT HELIX 154 157
FT TURN 158 162
FT STRAND 165 167
FT HELIX 170 180
FT TURN 181 183
FT STRAND 184 186
FT HELIX 189 191
FT HELIX 193 201
FT TURN 202 206
FT HELIX 211 223
FT TURN 227 231
FT HELIX 232 253
FT HELIX 256 269
FT HELIX 271 274
FT TURN 275 277
FT TURN 280 282
FT HELIX 283 294
FT TURN 295 297
FT HELIX 300 304
FT HELIX 307 311
FT TURN 312 314
FT HELIX 316 328
FT HELIX 332 352
FT HELIX 355 357
FT TURN 358 360
FT HELIX 361 377
FT TURN 378 382
FT HELIX 384 398
FT HELIX 404 417
FT HELIX 421 423
FT HELIX 429 440
FT HELIX 446 462
FT HELIX 469 480
FT TURN 481 483
FT TURN 485 488
FT HELIX 489 513
FT STRAND 522 529
FT TURN 530 532
FT HELIX 545 559
FT STRAND 564 566
FT HELIX 571 573
FT STRAND 575 579
FT STRAND 588 592
FT HELIX 593 601
FT HELIX 610 616
FT HELIX 621 629
FT TURN 630 636
FT STRAND 638 641
FT STRAND 645 647
FT STRAND 653 656
FT STRAND 665 668
FT HELIX 670 674
FT HELIX 678 706
FT STRAND 707 711
FT HELIX 713 722
FT STRAND 723 725
FT HELIX 729 741
FT STRAND 754 756
SQ SEQUENCE 759 AA; 87680 MW; 3C4C6A1BBD94D51B CRC64;
MADEAPRKGS FSALVGRTNG LTKPAALAAA PAKPGGAGGS KKLVIKNFRD RPRLPDNYTQ
DTWRKLHEAV RAVQSSTSIR YNLEELYQAV ENLCSHKVSP MLYKQLRQAC EDHVQAQILP
FREDSLDSVL FLKKINTCWQ DHCRQMIMIR SIFLFLDRTY VLQNSTLPSI WDMGLELFRT
HIISDKMVQS KTIDGILLLI ERERSGEAVD RSLLRSLLGM LSDLQVYKDS FELKFLEETN
CLYAAEGQRL MQEREVPEYL NHVSKRLEEE GDRVITYLDH STQKPLIACV EKQLLGEHLT
AILQKGLDHL LDENRVPDLA QMYQLFSRVR GGQQALLQHW SEYIKTFGTA IVINPEKDKD
MVQDLLDFKD KVDHVIEVCF QKNERFVNLM KESFETFINK RPNKPAELIA KHVDSKLRAG
NKEATDEELE RTLDKIMILF RFIHGKDVFE AFYKKDLAKR LLVGKSASVD AEKSMLSKLK
HECGAAFTSK LEGMFKDMEL SKDIMVHFKQ HMQNQSDSGP IDLTVNILTM GYWPTYTPME
VHLTPEMIKL QEVFKAFYLG KHSGRKLQWQ TTLGHAVLKA EFKEGKKEFQ VSLFQTLVLL
MFNEGDGFSF EEIKMATGIE DSELRRTLQS LACGKARVLI KSPKGKEVED GDKFIFNGEF
KHKLFRIKIN QIQMKETVEE QVSTTERVFQ DRQYQIDAAI VRIMKMRKTL GHNLLVSELY
NQLKFPVKPG DLKKRIESLI DRDYMERDKD NPNQYHYVA
//
MIM
603137
*RECORD*
*FIELD* NO
603137
*FIELD* TI
*603137 CULLIN 4A; CUL4A
*FIELD* TX
DESCRIPTION
CUL4A is the ubiquitin ligase component of a multimeric complex involved
read morein the degradation of DNA damage-response proteins (Liu et al., 2009).
CLONING
Kipreos et al. (1996) identified the cullin gene family, which includes
at least 5 members in nematodes, 6 in humans, and 3 in S. cerevisiae.
Human CUL4A and CUL4B (300304) are orthologs of nematode Cul4. The
partial C-terminal amino acid sequences of CUL4A and CUL4B share 88%
identity. Osaka et al. (1998) also reported a partial CUL4A cDNA
sequence.
Using differential display to identify genes upregulated in breast
cancer cell lines, followed by database analysis, Chen et al. (1998)
cloned full-length human CUL4A. The deduced 659-amino acid protein
shares 30% identity with C. elegans Cul4. Chen et al. (1998) also
identified a CUL4A variant with an alternative 3-prime UTR. Northern
blot analysis detected 3.5- and 3.8-kb CUL4A transcripts in all normal
tissues examined and in normal breast epithelial cells and breast cancer
cell lines. In normal tissues, expression was highest in heart and
skeletal muscle and lowest in kidney and lung.
Michel and Xiong (1998) isolated a mouse Cul4a cDNA and reported that
the predicted protein contains 759 amino acids.
GENE FUNCTION
Osaka et al. (1998) characterized the pathway for modification by the
ubiquitin-like NEDD8 (603171) and identified CUL4A as a major target
protein for NEDD8 conjugation.
Zhong et al. (2003) showed that the CUL4 ubiquitin ligase temporally
restricts DNA replication licensing in Caenorhabditis elegans.
Inactivation of CUL4 causes massive DNA rereplication, producing cells
with up to 100C DNA content. The C. elegans ortholog of the
replication-licensing factor Cdt1 (605525) is required for DNA
replication. C. elegans CDT1 is present in G1-phase nuclei but
disappears as cells enter S phase. In cells lacking CUL4, CDT1 levels
failed to decrease during S phase and instead remained constant in the
rereplicating cells. Removal of 1 genomic copy of CDT1 suppressed the
CUL4 rereplication phenotype. Zhong et al. (2003) proposed that CUL4
prevents aberrant reinitiation of DNA replication, at least in part, by
facilitating the degradation of CDT1.
Wertz et al. (2004) reported that human DET1 (608727) promotes
ubiquitination and degradation of the protooncogenic transcription
factor c-Jun (165160) by assembling a multisubunit ubiquitin ligase
containing DNA damage-binding protein-1 (DDB1; 600045), CUL4A, regulator
of cullins-1 (ROC1; 603814), and constitutively photomorphogenic-1
(COP1; 608067). Ablation of any subunit by RNA interference stabilized
c-Jun and increased c-Jun-activated transcription. Wertz et al. (2004)
concluded that their findings characterized a c-Jun ubiquitin ligase and
define a specific function for DET1 in mammalian cells.
By mass spectrometric analysis, Higa et al. (2006) identified over 20
WD40 repeat-containing (WDR) proteins that interacted with the
CUL4-DDB1-ROC1 complex. Sequence alignment revealed that most of the
interacting WDR proteins had a centrally positioned WDxR/K submotif.
Knockdown studies suggested that the WDR proteins functioned as
substrate-specific adaptors. For example, inactivation of L2DTL (DTL;
610617), but not other WDR proteins, prevented CUL4-DDB1-dependent
proteolysis of CDT1 following gamma irradiation. Inactivation of WDR5
(609012) or EED (605984), but not other WDR proteins, altered the
pattern of CUL4-DDB1-dependent histone H3 (see 602810) methylation.
Ito et al. (2010) demonstrated that cereblon (CRBN; 609262) forms an E3
ubiquitin ligase complex with CUL4A and DDB1 that is important for limb
outgrowth and expression of the fibroblast growth factor receptor FGF8
(600483) in zebrafish and chicks. Thalidomide initiates its teratogenic
effects by binding to CRBN and inhibiting the associated ubiquitin
ligase activity. Ito et al. (2010) concluded that their study revealed a
basis for thalidomide teratogenicity and may contribute to the
development of thalidomide derivatives without teratogenic activity.
BIOCHEMICAL FEATURES
- Crystal Structure
Angers et al. (2006) presented crystallographic analyses of a virally
hijacked form of the human DDB1-CUL4A-ROC1 machinery, which showed that
DDB1 uses 1 beta-propeller domain for cullin scaffold binding and a
variably attached separate double-beta-propeller fold for substrate
presentation. Through tandem-affinity purification of human DDB1 and
CUL4A complexes followed by mass spectrometry analysis, Angers et al.
(2006) identified a novel family of WD40-repeat proteins, which directly
bind to the double-propeller fold of DDB1 and serve as the
substrate-recruiting module of the E3. Together, Angers et al. (2006)
concluded that their structural and proteomic results reveal the
structural mechanisms and molecular logic underlying the assembly and
versatility of a new family of cullin-RING E3 complexes.
MAPPING
Using human-rodent somatic cell hybrids and FISH, Chen et al. (1998)
mapped the CUL4A gene to chromosome 13q34-qter.
ANIMAL MODEL
Li et al. (2002) found that knockout of Cul4a in mice via deletion of
exon 1 resulted in embryonic lethality. However, Liu et al. (2009)
showed that the lethality observed by Li et al. (2002) likely resulted
from concomitant disruption of the critical Pcid2 gene (613713), which
partly overlaps with Cul4a on the opposite strand. Liu et al. (2009)
found that mice homozygous for a Cul4a loss-of-function allele (exon 17
to 19 knockout) displayed no overt developmental abnormalities
throughout their life span. Skin-specific deletion of Cul4a resulted in
dramatically enhanced resistance to ultraviolet (UV) radiation-induced
skin carcinogenesis. Consistent with this, Cul4a deletion led to
increased accumulation of the DNA damage sensors Ddb2 (600811) and Xpc
(613208) and the G1/S checkpoint effector p21 (CDKN1A; 116899),
resulting in enhanced DNA repair activity and reinforced UV-responsive
DNA damage checkpoint. Liu et al. (2009) concluded that CUL4A restricts
cellular DNA repair capacity by degrading DNA damage sensors and
checkpoint effectors.
Kopanja et al. (2009) showed that conditional deletion of Cul4a in mice
resulted in aberrant cell proliferation in vitro and in vivo. Deletion
of Cul4a in mouse liver caused accumulation of p53 (TP53; 191170) and
p27(Kip1) (CDKN1B; 600778). Cul4a-deleted cells were retarded in their
progression through the S and early M phases of the cell cycle, and
expression of a dominant-negative mutant of p53 reversed these defects.
Cul4a-deleted cells also showed an aberrant number of centrosomes,
multipolar spindles, micronuclei, increased sensitivity to ultraviolet
radiation, and deficient nucleotide excision repair.
*FIELD* RF
1. Angers, S.; Li, T.; Yi, X.; MacCoss, M. J.; Moon, R. T.; Zheng,
N.: Molecular architecture and assembly of the DDB1-CUL4A ubiquitin
ligase machinery. Nature 443: 590-593, 2006.
2. Chen, L.-C.; Manjeshwar, S.; Lu, Y.; Moore, D.; Ljung, B.-M.; Kuo,
W.-L.; Dairkee, S. H.; Wernick, M.; Collins, C.; Smith, H. S.: The
human homologue for the Caenorhabditis elegans cul-4 gene is amplified
and overexpressed in primary breast cancers. Cancer Res. 58: 3677-3683,
1998.
3. Higa, L. A.; Wu, M.; Ye, T.; Kobayashi, R.; Sun, H.; Zhang, H.
: CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins
and regulates histone methylation. Nature Cell Biol. 8: 1277-1283,
2006.
4. Ito, T.; Ando, H.; Suzuki, T.; Ogura, T.; Hotta, K.; Imamura, Y.;
Yamaguchi, Y.; Handa, H.: Identification of a primary target of thalidomide
teratogenicity. Science 327: 1345-1350, 2010.
5. Kipreos, E. T.; Lander, L. E.; Wing, J. P.; He, W. W.; Hedgecock,
E. M.: cul-1 is required for cell cycle exit in C. elegans and identifies
a novel gene family. Cell 85: 829-839, 1996.
6. Kopanja, D.; Stoyanova, T.; Okur, M. N.; Huang, E.; Bagchi, S.;
Raychaudhuri, P.: Proliferation defects and genome instability in
cells lacking Cul4A. Oncogene 28: 2456-2465, 2009.
7. Li, B.; Ruiz, J. C.; Chun, K. T.: CUL-4A is critical for early
embryonic development. Molec. Cell. Biol. 22: 4997-5005, 2002.
8. Liu, L.; Lee, S.; Zhang, J.; Peters, S. B.; Hannah, J.; Zhang,
Y.; Yin, Y.; Koff, A.; Ma, L.; Zhou, P.: CUL4A abrogation augments
DNA damage response and protection against skin carcinogenesis. Molec.
Cell 34: 451-460, 2009.
9. Michel, J. J.; Xiong, Y.: Human CUL-1, but not other cullin family
members, selectively interacts with SKP1 to form a complex with SKP2
and cyclin A. Cell Growth Differ. 9: 435-449, 1998.
10. Osaka, F.; Kawasaki, H.; Aida, N.; Saeki, M.; Chiba, T.; Kawashima,
S.; Tanaka, K.; Kato, S.: A new NEDD8-ligating system for cullin-4A. Genes
Dev. 12: 2263-2268, 1998.
11. Wertz, I. E.; O'Rourke, K. M.; Zhang, Z.; Dornan, D.; Arnott,
D.; Deshaies, R. J.; Dixit, V. M.: Human de-etiolated-1 regulates
c-Jun by assembling a CUL4A ubiquitin ligase. Science 303: 1371-1374,
2004.
12. Zhong, W.; Feng, H.; Santiago, F. E.; Kipreos, E. T.: CUL-4 ubiquitin
ligase maintains genome stability by restraining DNA-replication licensing. Nature 423:
885-889, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 03/05/2013
Patricia A. Hartz - updated: 8/30/2010
Ada Hamosh - updated: 4/13/2010
Patricia A. Hartz - updated: 10/20/2009
Ada Hamosh - updated: 10/24/2006
Ada Hamosh - updated: 6/10/2004
Ada Hamosh - updated: 7/8/2003
*FIELD* CD
Rebekah S. Rasooly: 10/13/1998
*FIELD* ED
mgross: 03/05/2013
mgross: 1/25/2011
mgross: 9/1/2010
terry: 8/30/2010
alopez: 4/15/2010
terry: 4/13/2010
carol: 1/12/2010
mgross: 10/28/2009
terry: 10/20/2009
alopez: 11/6/2006
terry: 10/24/2006
alopez: 6/11/2004
terry: 6/10/2004
alopez: 7/9/2003
terry: 7/8/2003
carol: 3/13/2001
alopez: 10/30/1998
dkim: 10/28/1998
psherman: 10/21/1998
alopez: 10/13/1998
*RECORD*
*FIELD* NO
603137
*FIELD* TI
*603137 CULLIN 4A; CUL4A
*FIELD* TX
DESCRIPTION
CUL4A is the ubiquitin ligase component of a multimeric complex involved
read morein the degradation of DNA damage-response proteins (Liu et al., 2009).
CLONING
Kipreos et al. (1996) identified the cullin gene family, which includes
at least 5 members in nematodes, 6 in humans, and 3 in S. cerevisiae.
Human CUL4A and CUL4B (300304) are orthologs of nematode Cul4. The
partial C-terminal amino acid sequences of CUL4A and CUL4B share 88%
identity. Osaka et al. (1998) also reported a partial CUL4A cDNA
sequence.
Using differential display to identify genes upregulated in breast
cancer cell lines, followed by database analysis, Chen et al. (1998)
cloned full-length human CUL4A. The deduced 659-amino acid protein
shares 30% identity with C. elegans Cul4. Chen et al. (1998) also
identified a CUL4A variant with an alternative 3-prime UTR. Northern
blot analysis detected 3.5- and 3.8-kb CUL4A transcripts in all normal
tissues examined and in normal breast epithelial cells and breast cancer
cell lines. In normal tissues, expression was highest in heart and
skeletal muscle and lowest in kidney and lung.
Michel and Xiong (1998) isolated a mouse Cul4a cDNA and reported that
the predicted protein contains 759 amino acids.
GENE FUNCTION
Osaka et al. (1998) characterized the pathway for modification by the
ubiquitin-like NEDD8 (603171) and identified CUL4A as a major target
protein for NEDD8 conjugation.
Zhong et al. (2003) showed that the CUL4 ubiquitin ligase temporally
restricts DNA replication licensing in Caenorhabditis elegans.
Inactivation of CUL4 causes massive DNA rereplication, producing cells
with up to 100C DNA content. The C. elegans ortholog of the
replication-licensing factor Cdt1 (605525) is required for DNA
replication. C. elegans CDT1 is present in G1-phase nuclei but
disappears as cells enter S phase. In cells lacking CUL4, CDT1 levels
failed to decrease during S phase and instead remained constant in the
rereplicating cells. Removal of 1 genomic copy of CDT1 suppressed the
CUL4 rereplication phenotype. Zhong et al. (2003) proposed that CUL4
prevents aberrant reinitiation of DNA replication, at least in part, by
facilitating the degradation of CDT1.
Wertz et al. (2004) reported that human DET1 (608727) promotes
ubiquitination and degradation of the protooncogenic transcription
factor c-Jun (165160) by assembling a multisubunit ubiquitin ligase
containing DNA damage-binding protein-1 (DDB1; 600045), CUL4A, regulator
of cullins-1 (ROC1; 603814), and constitutively photomorphogenic-1
(COP1; 608067). Ablation of any subunit by RNA interference stabilized
c-Jun and increased c-Jun-activated transcription. Wertz et al. (2004)
concluded that their findings characterized a c-Jun ubiquitin ligase and
define a specific function for DET1 in mammalian cells.
By mass spectrometric analysis, Higa et al. (2006) identified over 20
WD40 repeat-containing (WDR) proteins that interacted with the
CUL4-DDB1-ROC1 complex. Sequence alignment revealed that most of the
interacting WDR proteins had a centrally positioned WDxR/K submotif.
Knockdown studies suggested that the WDR proteins functioned as
substrate-specific adaptors. For example, inactivation of L2DTL (DTL;
610617), but not other WDR proteins, prevented CUL4-DDB1-dependent
proteolysis of CDT1 following gamma irradiation. Inactivation of WDR5
(609012) or EED (605984), but not other WDR proteins, altered the
pattern of CUL4-DDB1-dependent histone H3 (see 602810) methylation.
Ito et al. (2010) demonstrated that cereblon (CRBN; 609262) forms an E3
ubiquitin ligase complex with CUL4A and DDB1 that is important for limb
outgrowth and expression of the fibroblast growth factor receptor FGF8
(600483) in zebrafish and chicks. Thalidomide initiates its teratogenic
effects by binding to CRBN and inhibiting the associated ubiquitin
ligase activity. Ito et al. (2010) concluded that their study revealed a
basis for thalidomide teratogenicity and may contribute to the
development of thalidomide derivatives without teratogenic activity.
BIOCHEMICAL FEATURES
- Crystal Structure
Angers et al. (2006) presented crystallographic analyses of a virally
hijacked form of the human DDB1-CUL4A-ROC1 machinery, which showed that
DDB1 uses 1 beta-propeller domain for cullin scaffold binding and a
variably attached separate double-beta-propeller fold for substrate
presentation. Through tandem-affinity purification of human DDB1 and
CUL4A complexes followed by mass spectrometry analysis, Angers et al.
(2006) identified a novel family of WD40-repeat proteins, which directly
bind to the double-propeller fold of DDB1 and serve as the
substrate-recruiting module of the E3. Together, Angers et al. (2006)
concluded that their structural and proteomic results reveal the
structural mechanisms and molecular logic underlying the assembly and
versatility of a new family of cullin-RING E3 complexes.
MAPPING
Using human-rodent somatic cell hybrids and FISH, Chen et al. (1998)
mapped the CUL4A gene to chromosome 13q34-qter.
ANIMAL MODEL
Li et al. (2002) found that knockout of Cul4a in mice via deletion of
exon 1 resulted in embryonic lethality. However, Liu et al. (2009)
showed that the lethality observed by Li et al. (2002) likely resulted
from concomitant disruption of the critical Pcid2 gene (613713), which
partly overlaps with Cul4a on the opposite strand. Liu et al. (2009)
found that mice homozygous for a Cul4a loss-of-function allele (exon 17
to 19 knockout) displayed no overt developmental abnormalities
throughout their life span. Skin-specific deletion of Cul4a resulted in
dramatically enhanced resistance to ultraviolet (UV) radiation-induced
skin carcinogenesis. Consistent with this, Cul4a deletion led to
increased accumulation of the DNA damage sensors Ddb2 (600811) and Xpc
(613208) and the G1/S checkpoint effector p21 (CDKN1A; 116899),
resulting in enhanced DNA repair activity and reinforced UV-responsive
DNA damage checkpoint. Liu et al. (2009) concluded that CUL4A restricts
cellular DNA repair capacity by degrading DNA damage sensors and
checkpoint effectors.
Kopanja et al. (2009) showed that conditional deletion of Cul4a in mice
resulted in aberrant cell proliferation in vitro and in vivo. Deletion
of Cul4a in mouse liver caused accumulation of p53 (TP53; 191170) and
p27(Kip1) (CDKN1B; 600778). Cul4a-deleted cells were retarded in their
progression through the S and early M phases of the cell cycle, and
expression of a dominant-negative mutant of p53 reversed these defects.
Cul4a-deleted cells also showed an aberrant number of centrosomes,
multipolar spindles, micronuclei, increased sensitivity to ultraviolet
radiation, and deficient nucleotide excision repair.
*FIELD* RF
1. Angers, S.; Li, T.; Yi, X.; MacCoss, M. J.; Moon, R. T.; Zheng,
N.: Molecular architecture and assembly of the DDB1-CUL4A ubiquitin
ligase machinery. Nature 443: 590-593, 2006.
2. Chen, L.-C.; Manjeshwar, S.; Lu, Y.; Moore, D.; Ljung, B.-M.; Kuo,
W.-L.; Dairkee, S. H.; Wernick, M.; Collins, C.; Smith, H. S.: The
human homologue for the Caenorhabditis elegans cul-4 gene is amplified
and overexpressed in primary breast cancers. Cancer Res. 58: 3677-3683,
1998.
3. Higa, L. A.; Wu, M.; Ye, T.; Kobayashi, R.; Sun, H.; Zhang, H.
: CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins
and regulates histone methylation. Nature Cell Biol. 8: 1277-1283,
2006.
4. Ito, T.; Ando, H.; Suzuki, T.; Ogura, T.; Hotta, K.; Imamura, Y.;
Yamaguchi, Y.; Handa, H.: Identification of a primary target of thalidomide
teratogenicity. Science 327: 1345-1350, 2010.
5. Kipreos, E. T.; Lander, L. E.; Wing, J. P.; He, W. W.; Hedgecock,
E. M.: cul-1 is required for cell cycle exit in C. elegans and identifies
a novel gene family. Cell 85: 829-839, 1996.
6. Kopanja, D.; Stoyanova, T.; Okur, M. N.; Huang, E.; Bagchi, S.;
Raychaudhuri, P.: Proliferation defects and genome instability in
cells lacking Cul4A. Oncogene 28: 2456-2465, 2009.
7. Li, B.; Ruiz, J. C.; Chun, K. T.: CUL-4A is critical for early
embryonic development. Molec. Cell. Biol. 22: 4997-5005, 2002.
8. Liu, L.; Lee, S.; Zhang, J.; Peters, S. B.; Hannah, J.; Zhang,
Y.; Yin, Y.; Koff, A.; Ma, L.; Zhou, P.: CUL4A abrogation augments
DNA damage response and protection against skin carcinogenesis. Molec.
Cell 34: 451-460, 2009.
9. Michel, J. J.; Xiong, Y.: Human CUL-1, but not other cullin family
members, selectively interacts with SKP1 to form a complex with SKP2
and cyclin A. Cell Growth Differ. 9: 435-449, 1998.
10. Osaka, F.; Kawasaki, H.; Aida, N.; Saeki, M.; Chiba, T.; Kawashima,
S.; Tanaka, K.; Kato, S.: A new NEDD8-ligating system for cullin-4A. Genes
Dev. 12: 2263-2268, 1998.
11. Wertz, I. E.; O'Rourke, K. M.; Zhang, Z.; Dornan, D.; Arnott,
D.; Deshaies, R. J.; Dixit, V. M.: Human de-etiolated-1 regulates
c-Jun by assembling a CUL4A ubiquitin ligase. Science 303: 1371-1374,
2004.
12. Zhong, W.; Feng, H.; Santiago, F. E.; Kipreos, E. T.: CUL-4 ubiquitin
ligase maintains genome stability by restraining DNA-replication licensing. Nature 423:
885-889, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 03/05/2013
Patricia A. Hartz - updated: 8/30/2010
Ada Hamosh - updated: 4/13/2010
Patricia A. Hartz - updated: 10/20/2009
Ada Hamosh - updated: 10/24/2006
Ada Hamosh - updated: 6/10/2004
Ada Hamosh - updated: 7/8/2003
*FIELD* CD
Rebekah S. Rasooly: 10/13/1998
*FIELD* ED
mgross: 03/05/2013
mgross: 1/25/2011
mgross: 9/1/2010
terry: 8/30/2010
alopez: 4/15/2010
terry: 4/13/2010
carol: 1/12/2010
mgross: 10/28/2009
terry: 10/20/2009
alopez: 11/6/2006
terry: 10/24/2006
alopez: 6/11/2004
terry: 6/10/2004
alopez: 7/9/2003
terry: 7/8/2003
carol: 3/13/2001
alopez: 10/30/1998
dkim: 10/28/1998
psherman: 10/21/1998
alopez: 10/13/1998