DDB2_MOUSE
ID DDB2_MOUSE Reviewed; 432 AA.
AC Q99J79;
DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=DNA damage-binding protein 2;
DE AltName: Full=Damage-specific DNA-binding protein 2;
GN Name=Ddb2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Plasmacytoma;
RX PubMed=10713455; DOI=10.1016/s0378-1119(00)00022-6;
RA Zolezzi F., Linn S.;
RT "Studies of the murine DDB1 and DDB2 genes.";
RL Gene 245:151-159(2000).
RN [2]
RP FUNCTION, INTERACTION WITH DDB2, AND PHOSPHORYLATION BY ABL1.
RX PubMed=12107171; DOI=10.1074/jbc.m204416200;
RA Cong F., Tang J., Hwang B.J., Vuong B.Q., Chu G., Goff S.P.;
RT "Interaction between UV-damaged DNA binding activity proteins and the c-Abl
RT tyrosine kinase.";
RL J. Biol. Chem. 277:34870-34878(2002).
RN [3]
RP DISRUPTION PHENOTYPE.
RX PubMed=14769931; DOI=10.1073/pnas.0306551101;
RA Itoh T., Cado D., Kamide R., Linn S.;
RT "DDB2 gene disruption leads to skin tumors and resistance to apoptosis
RT after exposure to ultraviolet light but not a chemical carcinogen.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:2052-2057(2004).
RN [4]
RP DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=15558025; DOI=10.1038/sj.onc.1208211;
RA Yoon T., Chakrabortty A., Franks R., Valli T., Kiyokawa H.,
RA Raychaudhuri P.;
RT "Tumor-prone phenotype of the DDB2-deficient mice.";
RL Oncogene 24:469-478(2005).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=17635991; DOI=10.1242/jcs.008367;
RA Luijsterburg M.S., Goedhart J., Moser J., Kool H., Geverts B.,
RA Houtsmuller A.B., Mullenders L.H.F., Vermeulen W., van Driel R.;
RT "Dynamic in vivo interaction of DDB2 E3 ubiquitin ligase with UV-damaged
RT DNA is independent of damage-recognition protein XPC.";
RL J. Cell Sci. 120:2706-2716(2007).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=17468495; DOI=10.1093/hmg/ddm107;
RA Itoh T., Iwashita S., Cohen M.B., Meyerholz D.K., Linn S.;
RT "Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ
RT cell apoptosis.";
RL Hum. Mol. Genet. 16:1578-1586(2007).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Protein, which is both involved in DNA repair and protein
CC ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box)
CC complexes, respectively (PubMed:12107171). Core component of the UV-DDB
CC complex (UV-damaged DNA-binding protein complex), a complex that
CC recognizes UV-induced DNA damage and recruit proteins of the nucleotide
CC excision repair pathway (the NER pathway) to initiate DNA repair (By
CC similarity). The UV-DDB complex preferentially binds to cyclobutane
CC pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and
CC short mismatches (By similarity). Also functions as the substrate
CC recognition module for the DCX (DDB2-CUL4-X-box) E3 ubiquitin-protein
CC ligase complex DDB2-CUL4-ROC1 (also known as CUL4-DDB-ROC1 and CUL4-
CC DDB-RBX1) (By similarity). The DDB2-CUL4-ROC1 complex may ubiquitinate
CC histone H2A, histone H3 and histone H4 at sites of UV-induced DNA
CC damage (By similarity). The ubiquitination of histones may facilitate
CC their removal from the nucleosome and promote subsequent DNA repair (By
CC similarity). The DDB2-CUL4-ROC1 complex also ubiquitinates XPC, which
CC may enhance DNA-binding by XPC and promote NER (By similarity). The
CC DDB2-CUL4-ROC1 complex also ubiquitinates KAT7/HBO1 in response to DNA
CC damage, leading to its degradation: recognizes KAT7/HBO1 following
CC phosphorylation by ATR (By similarity). {ECO:0000250|UniProtKB:Q92466,
CC ECO:0000269|PubMed:12107171}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Component of the UV-DDB complex which includes DDB1 and DDB2.
CC The UV-DDB complex interacts with monoubiquitinated histone H2A and
CC binds to XPC via the DDB2 subunit. Component of the DCX (DDB1-CUL4-X-
CC box) E3 ubiquitin-protein ligase complex DDB1-CUL4-ROC1 (also known as
CC CUL4-DDB-ROC1 and CUL4-DDB-RBX1), which includes CUL4A or CUL4B, DDB1,
CC DDB2 and RBX1. DDB2 may function as the substrate recognition module
CC within this complex. The DDB1-CUL4-ROC1 complex may associate with the
CC COP9 signalosome, and this inhibits the E3 ubiquitin-protein ligase
CC activity of the complex. A large number of other DCX complexes may also
CC exist in which an alternate substrate targeting subunit replaces DDB2.
CC These targeting subunits are generally known as DCAF (DDB1- and CUL4-
CC associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins
CC (By similarity). {ECO:0000250|UniProtKB:Q92466}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:17635991}. Chromosome
CC {ECO:0000250|UniProtKB:Q92466}. Note=Accumulates at sites of DNA damage
CC following UV irradiation. {ECO:0000250|UniProtKB:Q92466}.
CC -!- TISSUE SPECIFICITY: Expressed in bone marrow, liver, lung, muscle,
CC pancreas and spleen. {ECO:0000269|PubMed:15558025}.
CC -!- DOMAIN: The DWD box is required for interaction with DDB1.
CC {ECO:0000250|UniProtKB:Q92466}.
CC -!- DOMAIN: Interblade loops of the WD repeat region mediate most of the
CC interaction with DNA. A hairpin between blades 5 and 6 inserts into DNA
CC minor groove and mediates recognition of lesions and separation of the
CC damaged and undamaged strands (By similarity).
CC {ECO:0000250|UniProtKB:Q92466}.
CC -!- PTM: Phosphorylation by ABL1 negatively regulate UV-DDB activity.
CC {ECO:0000269|PubMed:12107171}.
CC -!- PTM: Ubiquitinated by CUL4A in response to UV irradiation.
CC Ubiquitination appears to both impair DNA-binding and promotes
CC ubiquitin-dependent proteolysis. Degradation of DDB2 at sites of DNA
CC damage may be a prerequisite for their recognition by XPC and
CC subsequent repair. CUL4A-mediated degradation appears to be promoted by
CC ABL1. {ECO:0000250|UniProtKB:Q92466}.
CC -!- PTM: Ubiquitinated, leading to proteasomal degradation, and
CC deubiquitinated by USP24. {ECO:0000250|UniProtKB:Q92466}.
CC -!- PTM: Acetylated. Deacetylation by SIRT6 in response to UV stress
CC facilitates nucleotide excision repair pathway (the NER pathway)
CC transduction. {ECO:0000250|UniProtKB:Q92466}.
CC -!- DISRUPTION PHENOTYPE: Mice exhibit elevated susceptibility to UV-
CC induced skin carcinogenesis and enhanced rates of spontaneous tumor
CC formation, particularly for lung and mammary adenocarcinomas. DDB2 is
CC haploinsufficient as a tumor suppressor. The spleens of these animals
CC are enlarged due to enhanced lymphoid proliferation while the testes
CC are also enlarged due to reduced rates of apoptosis of testicular germ
CC cells. Fibroblasts from these animals are resistant to p53-dependent
CC apoptosis induced by UV treatment. {ECO:0000269|PubMed:14769931,
CC ECO:0000269|PubMed:15558025, ECO:0000269|PubMed:17468495}.
CC -!- SIMILARITY: Belongs to the WD repeat DDB2/WDR76 family. {ECO:0000305}.
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DR EMBL; AY027937; AAK16810.1; -; mRNA.
DR CCDS; CCDS16428.1; -.
DR RefSeq; NP_082395.2; NM_028119.5.
DR AlphaFoldDB; Q99J79; -.
DR SMR; Q99J79; -.
DR BioGRID; 223741; 1.
DR ComplexPortal; CPX-1122; UV DNA damage recognition complex DBB1-DBB2.
DR ComplexPortal; CPX-650; CRL4-DDB2 E3 ubiquitin ligase complex, CUL4A variant.
DR ComplexPortal; CPX-651; CRL4-DDB2 E3 ubiquitin ligase complex, CUL4B variant.
DR STRING; 10090.ENSMUSP00000028696; -.
DR iPTMnet; Q99J79; -.
DR PhosphoSitePlus; Q99J79; -.
DR EPD; Q99J79; -.
DR MaxQB; Q99J79; -.
DR PaxDb; Q99J79; -.
DR PeptideAtlas; Q99J79; -.
DR PRIDE; Q99J79; -.
DR ProteomicsDB; 279843; -.
DR Antibodypedia; 13582; 283 antibodies from 34 providers.
DR DNASU; 107986; -.
DR Ensembl; ENSMUST00000028696; ENSMUSP00000028696; ENSMUSG00000002109.
DR GeneID; 107986; -.
DR KEGG; mmu:107986; -.
DR UCSC; uc008kvh.2; mouse.
DR CTD; 1643; -.
DR MGI; MGI:1355314; Ddb2.
DR VEuPathDB; HostDB:ENSMUSG00000002109; -.
DR eggNOG; KOG4328; Eukaryota.
DR GeneTree; ENSGT00510000047881; -.
DR InParanoid; Q99J79; -.
DR OMA; FIKGKGP; -.
DR OrthoDB; 559605at2759; -.
DR PhylomeDB; Q99J79; -.
DR TreeFam; TF331587; -.
DR Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR Reactome; R-MMU-5696394; DNA Damage Recognition in GG-NER.
DR Reactome; R-MMU-5696395; Formation of Incision Complex in GG-NER.
DR Reactome; R-MMU-5696400; Dual Incision in GG-NER.
DR Reactome; R-MMU-8951664; Neddylation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 107986; 4 hits in 109 CRISPR screens.
DR ChiTaRS; Ddb2; mouse.
DR PRO; PR:Q99J79; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q99J79; protein.
DR Bgee; ENSMUSG00000002109; Expressed in paneth cell and 245 other tissues.
DR ExpressionAtlas; Q99J79; baseline and differential.
DR Genevisible; Q99J79; MM.
DR GO; GO:0030054; C:cell junction; ISO:MGI.
DR GO; GO:0080008; C:Cul4-RING E3 ubiquitin ligase complex; ISO:MGI.
DR GO; GO:0031464; C:Cul4A-RING E3 ubiquitin ligase complex; IC:ComplexPortal.
DR GO; GO:0031465; C:Cul4B-RING E3 ubiquitin ligase complex; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0090734; C:site of DNA damage; ISS:UniProtKB.
DR GO; GO:0003684; F:damaged DNA binding; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISO:MGI.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IC:ComplexPortal.
DR GO; GO:0034644; P:cellular response to UV; IC:ComplexPortal.
DR GO; GO:0006281; P:DNA repair; IBA:GO_Central.
DR GO; GO:0035518; P:histone H2A monoubiquitination; ISO:MGI.
DR GO; GO:0006289; P:nucleotide-excision repair; ISS:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; ISO:MGI.
DR GO; GO:0000209; P:protein polyubiquitination; ISO:MGI.
DR GO; GO:0006290; P:pyrimidine dimer repair; IMP:MGI.
DR GO; GO:0009411; P:response to UV; ISO:MGI.
DR GO; GO:0070914; P:UV-damage excision repair; ISO:MGI.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR033312; DDB2.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom_sf.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR019775; WD40_repeat_CS.
DR InterPro; IPR036322; WD40_repeat_dom_sf.
DR PANTHER; PTHR15169; PTHR15169; 1.
DR Pfam; PF00400; WD40; 2.
DR SMART; SM00320; WD40; 5.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; 1.
DR PROSITE; PS50082; WD_REPEATS_2; 1.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Acetylation; Chromosome; DNA damage; DNA repair; DNA-binding; Nucleus;
KW Reference proteome; Repeat; Ubl conjugation; Ubl conjugation pathway;
KW WD repeat.
FT CHAIN 1..432
FT /note="DNA damage-binding protein 2"
FT /id="PRO_0000050954"
FT REPEAT 116..151
FT /note="WD 1"
FT REPEAT 159..194
FT /note="WD 2"
FT REPEAT 203..238
FT /note="WD 3"
FT REPEAT 244..287
FT /note="WD 4"
FT REPEAT 290..329
FT /note="WD 5"
FT REPEAT 343..386
FT /note="WD 6"
FT REPEAT 396..420
FT /note="WD 7"
FT REGION 1..31
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 68..79
FT /note="Required for interaction with DDB1"
FT /evidence="ECO:0000250|UniProtKB:Q92466"
FT REGION 87..98
FT /note="Required for interaction with DDB1"
FT /evidence="ECO:0000250|UniProtKB:Q92466"
FT REGION 334..336
FT /note="Photolesion recognition"
FT /evidence="ECO:0000250"
FT MOTIF 256..274
FT /note="DWD box"
FT /evidence="ECO:0000250|UniProtKB:Q92466"
FT MOD_RES 35
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q92466"
FT MOD_RES 77
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q92466"
SQ SEQUENCE 432 AA; 48375 MW; 9E717FE4DAAA57B2 CRC64;
MAPKKCPETQ KSPDVAVLLR SKSRRGPQEL EPEAKKLRVQ GPVSSRTCES CCLLAELSSL
QIPSRSSSIV RDLYQHKLGK ATWSSLQQGL QKSFLHSLAS YQVFRKAAPF DRRTTSLAWH
PTHPSTLAVG SKGGDIMIWN FGIKDKPIFL KGIGAGGSIT GLKFNHLNTN QFFASSMEGT
TRLQDFKGNI LRVYTSSNSC KVWFCSLDVS AKSRVVVTGD NMGHVILLST DGKELWNLRM
HKKKVAHVAL NPCCDWLLAT ASIDQTVKIW DLRQIKGKDS FLYSLPHRHP VNAACFSPDG
ARLLTTDQNN EIRVYSASQW DSPLNLISHP HRHFQHLTPI KATWHSRHNL IVVGRYPDPN
LKSCVPYELR TIDVFDGSSG KMMCQLYDPG YSGITSLNEF NPMGDTLAST MGYHILIWSQ
EEDGSQKDHE RL
