UniProt functional annotation for Q92466



	UniProt functional annotation for Q92466

UniProt code: Q92466.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Protein, which is both involved in DNA repair and protein ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes, respectively (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:9892649, PubMed:12732143, PubMed:15882621, PubMed:16473935, PubMed:18593899). Core component of the UV-DDB complex (UV-damaged DNA-binding protein complex), a complex that recognizes UV- induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:16260596, PubMed:12944386, PubMed:14751237). The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:16260596, PubMed:12944386). Also functions as the substrate recognition module for the DCX (DDB2- CUL4-X-box) E3 ubiquitin-protein ligase complex DDB2-CUL4-ROC1 (also known as CUL4-DDB-ROC1 and CUL4-DDB-RBX1) (PubMed:12732143, PubMed:15882621, PubMed:16473935, PubMed:18593899, PubMed:26572825). The DDB2-CUL4-ROC1 complex may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage (PubMed:16678110, PubMed:16473935). The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair (PubMed:16678110, PubMed:16473935). The DDB2-CUL4-ROC1 complex also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER (PubMed:15882621). The DDB2-CUL4-ROC1 complex also ubiquitinates KAT7/HBO1 in response to DNA damage, leading to its degradation: recognizes KAT7/HBO1 following phosphorylation by ATR (PubMed:26572825). {ECO:0000269|PubMed:10882109, ECO:0000269|PubMed:11278856, ECO:0000269|PubMed:11705987, ECO:0000269|PubMed:12732143, ECO:0000269|PubMed:12944386, ECO:0000269|PubMed:14751237, ECO:0000269|PubMed:15882621, ECO:0000269|PubMed:16260596, ECO:0000269|PubMed:16473935, ECO:0000269|PubMed:16678110, ECO:0000269|PubMed:18593899, ECO:0000269|PubMed:26572825, ECO:0000269|PubMed:9892649}.

Function: [Isoform D1]: Inhibits UV-damaged DNA repair. {ECO:0000269|PubMed:14751237}.

Function: [Isoform D2]: Inhibits UV-damaged DNA repair. {ECO:0000269|PubMed:14751237}.

Pathway: Protein modification; protein ubiquitination.

Subunit: Component of the UV-DDB complex which includes DDB1 and DDB2. The UV-DDB complex interacts with monoubiquitinated histone H2A and binds to XPC via the DDB2 subunit. Component of the DCX (DDB1-CUL4-X- box) E3 ubiquitin-protein ligase complex DDB1-CUL4-ROC1 (also known as CUL4-DDB-ROC1 and CUL4-DDB-RBX1), which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1. DDB2 may function as the substrate recognition module within this complex. The DDB1-CUL4-ROC1 complex may associate with the COP9 signalosome, and this inhibits the E3 ubiquitin-protein ligase activity of the complex. A large number of other DCX complexes may also exist in which an alternate substrate targeting subunit replaces DDB2. These targeting subunits are generally known as DCAF (DDB1- and CUL4- associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins. Isoform D1 and isoform D2 do not interact with DDB1. {ECO:0000269|PubMed:11673459, ECO:0000269|PubMed:12732143, ECO:0000269|PubMed:14751237, ECO:0000269|PubMed:15882621, ECO:0000269|PubMed:16223728, ECO:0000269|PubMed:16260596, ECO:0000269|PubMed:16473935, ECO:0000269|PubMed:16527807, ECO:0000269|PubMed:16678110, ECO:0000269|PubMed:16949367, ECO:0000269|PubMed:16964240, ECO:0000269|PubMed:17041588, ECO:0000269|PubMed:17079684, ECO:0000269|PubMed:18593899, ECO:0000269|PubMed:19109893, ECO:0000269|PubMed:19966799, ECO:0000269|PubMed:22822215, ECO:0000269|PubMed:9632823}.

Subcellular location: Nucleus {ECO:0000269|PubMed:10777490, ECO:0000269|PubMed:10777491, ECO:0000269|PubMed:11705987, ECO:0000269|PubMed:12944386, ECO:0000269|PubMed:14751237, ECO:0000269|PubMed:16473935, ECO:0000269|PubMed:16713579, ECO:0000269|PubMed:17635991, ECO:0000269|PubMed:18593899}. Note=Accumulates at sites of DNA damage following UV irradiation.

Tissue specificity: Ubiquitously expressed; with highest levels in corneal endothelium and lowest levels in brain. Isoform D1 is highly expressed in brain and heart. Isoform D2, isoform D3 and isoform D4 are weakly expressed. {ECO:0000269|PubMed:14751237}.

Induction: Expression is induced in response to treatment with IR or UV and this requires p53/TP53 activity. {ECO:0000269|PubMed:10777490}.

Domain: The DWD box is required for interaction with DDB1. {ECO:0000269|PubMed:17079684}.

Domain: Interblade loops of the WD repeat region mediate most of the interaction with DNA. A hairpin between blades 5 and 6 inserts into DNA minor groove and mediates recognition of lesions and separation of the damaged and undamaged strands. {ECO:0000269|PubMed:17079684}.

Ptm: Phosphorylation by ABL1 negatively regulate UV-DDB activity. {ECO:0000250}.

Ptm: Ubiquitinated by CUL4A in response to UV irradiation. Ubiquitination appears to both impair DNA-binding and promotes ubiquitin-dependent proteolysis. Degradation of DDB2 at sites of DNA damage may be a prerequisite for their recognition by XPC and subsequent repair. CUL4A-mediated degradation appears to be promoted by ABL1. {ECO:0000269|PubMed:23159851}.

Ptm: Ubiquitinated, leading to proteasomal degradation, and deubiquitinated by USP24. {ECO:0000269|PubMed:23159851}.

Disease: Xeroderma pigmentosum complementation group E (XP-E) [MIM:278740]: An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling and other pigmentation abnormalities. XP-E patients show a mild phenotype with minimal or no neurologic features. {ECO:0000269|PubMed:8798680}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the WD repeat DDB2/WDR76 family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Protein, which is both involved in DNA repair and protein ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes, respectively (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:9892649, PubMed:12732143, PubMed:15882621, PubMed:16473935, PubMed:18593899). Core component of the UV-DDB complex (UV-damaged DNA-binding protein complex), a complex that recognizes UV- induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:16260596, PubMed:12944386, PubMed:14751237). The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches (PubMed:10882109, PubMed:11278856, PubMed:11705987, PubMed:16260596, PubMed:12944386). Also functions as the substrate recognition module for the DCX (DDB2- CUL4-X-box) E3 ubiquitin-protein ligase complex DDB2-CUL4-ROC1 (also known as CUL4-DDB-ROC1 and CUL4-DDB-RBX1) (PubMed:12732143, PubMed:15882621, PubMed:16473935, PubMed:18593899, PubMed:26572825). The DDB2-CUL4-ROC1 complex may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage (PubMed:16678110, PubMed:16473935). The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair (PubMed:16678110, PubMed:16473935). The DDB2-CUL4-ROC1 complex also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER (PubMed:15882621). The DDB2-CUL4-ROC1 complex also ubiquitinates KAT7/HBO1 in response to DNA damage, leading to its degradation: recognizes KAT7/HBO1 following phosphorylation by ATR (PubMed:26572825). {ECO:0000269\|PubMed:10882109, ECO:0000269\|PubMed:11278856, ECO:0000269\|PubMed:11705987, ECO:0000269\|PubMed:12732143, ECO:0000269\|PubMed:12944386, ECO:0000269\|PubMed:14751237, ECO:0000269\|PubMed:15882621, ECO:0000269\|PubMed:16260596, ECO:0000269\|PubMed:16473935, ECO:0000269\|PubMed:16678110, ECO:0000269\|PubMed:18593899, ECO:0000269\|PubMed:26572825, ECO:0000269\|PubMed:9892649}.



Function:		[Isoform D1]: Inhibits UV-damaged DNA repair. {ECO:0000269\|PubMed:14751237}.



Function:		[Isoform D2]: Inhibits UV-damaged DNA repair. {ECO:0000269\|PubMed:14751237}.


Pathway:		Protein modification; protein ubiquitination.
Subunit:		Component of the UV-DDB complex which includes DDB1 and DDB2. The UV-DDB complex interacts with monoubiquitinated histone H2A and binds to XPC via the DDB2 subunit. Component of the DCX (DDB1-CUL4-X- box) E3 ubiquitin-protein ligase complex DDB1-CUL4-ROC1 (also known as CUL4-DDB-ROC1 and CUL4-DDB-RBX1), which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1. DDB2 may function as the substrate recognition module within this complex. The DDB1-CUL4-ROC1 complex may associate with the COP9 signalosome, and this inhibits the E3 ubiquitin-protein ligase activity of the complex. A large number of other DCX complexes may also exist in which an alternate substrate targeting subunit replaces DDB2. These targeting subunits are generally known as DCAF (DDB1- and CUL4- associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins. Isoform D1 and isoform D2 do not interact with DDB1. {ECO:0000269\|PubMed:11673459, ECO:0000269\|PubMed:12732143, ECO:0000269\|PubMed:14751237, ECO:0000269\|PubMed:15882621, ECO:0000269\|PubMed:16223728, ECO:0000269\|PubMed:16260596, ECO:0000269\|PubMed:16473935, ECO:0000269\|PubMed:16527807, ECO:0000269\|PubMed:16678110, ECO:0000269\|PubMed:16949367, ECO:0000269\|PubMed:16964240, ECO:0000269\|PubMed:17041588, ECO:0000269\|PubMed:17079684, ECO:0000269\|PubMed:18593899, ECO:0000269\|PubMed:19109893, ECO:0000269\|PubMed:19966799, ECO:0000269\|PubMed:22822215, ECO:0000269\|PubMed:9632823}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:10777490, ECO:0000269\|PubMed:10777491, ECO:0000269\|PubMed:11705987, ECO:0000269\|PubMed:12944386, ECO:0000269\|PubMed:14751237, ECO:0000269\|PubMed:16473935, ECO:0000269\|PubMed:16713579, ECO:0000269\|PubMed:17635991, ECO:0000269\|PubMed:18593899}. Note=Accumulates at sites of DNA damage following UV irradiation.
Tissue specificity:		Ubiquitously expressed; with highest levels in corneal endothelium and lowest levels in brain. Isoform D1 is highly expressed in brain and heart. Isoform D2, isoform D3 and isoform D4 are weakly expressed. {ECO:0000269\|PubMed:14751237}.
Induction:		Expression is induced in response to treatment with IR or UV and this requires p53/TP53 activity. {ECO:0000269\|PubMed:10777490}.
Domain:		The DWD box is required for interaction with DDB1. {ECO:0000269\|PubMed:17079684}.
Domain:		Interblade loops of the WD repeat region mediate most of the interaction with DNA. A hairpin between blades 5 and 6 inserts into DNA minor groove and mediates recognition of lesions and separation of the damaged and undamaged strands. {ECO:0000269\|PubMed:17079684}.
Ptm:		Phosphorylation by ABL1 negatively regulate UV-DDB activity. {ECO:0000250}.
Ptm:		Ubiquitinated by CUL4A in response to UV irradiation. Ubiquitination appears to both impair DNA-binding and promotes ubiquitin-dependent proteolysis. Degradation of DDB2 at sites of DNA damage may be a prerequisite for their recognition by XPC and subsequent repair. CUL4A-mediated degradation appears to be promoted by ABL1. {ECO:0000269\|PubMed:23159851}.
Ptm:		Ubiquitinated, leading to proteasomal degradation, and deubiquitinated by USP24. {ECO:0000269\|PubMed:23159851}.
Disease:		Xeroderma pigmentosum complementation group E (XP-E) [MIM:278740]: An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling and other pigmentation abnormalities. XP-E patients show a mild phenotype with minimal or no neurologic features. {ECO:0000269\|PubMed:8798680}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the WD repeat DDB2/WDR76 family. {ECO:0000305}.