UniProt functional annotation for P18074



	UniProt functional annotation for P18074

UniProt code: P18074.

Organism: Homo sapiens (Human).

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

Function: ATP-dependent 5'-3' DNA helicase, component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The ATP-dependent helicase activity of XPD/ERCC2 is required for DNA opening. In transcription, TFIIH has an essential role in transcription initiation. When the pre- initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. XPD/ERCC2 acts by forming a bridge between CAK and the core-TFIIH complex. Involved in the regulation of vitamin-D receptor activity. As part of the mitotic spindle-associated MMXD complex it plays a role in chromosome segregation. Might have a role in aging process and could play a causative role in the generation of skin cancers. {ECO:0000269|PubMed:10024882, ECO:0000269|PubMed:15494306, ECO:0000269|PubMed:20797633, ECO:0000269|PubMed:8413672}.

Catalytic activity: Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.12;

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:22678361};

Cofactor: Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883; Evidence={ECO:0000269|PubMed:22678361}; Note=Binds 1 [4Fe-4S] cluster. {ECO:0000269|PubMed:22678361};

Subunit: Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK- activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription. The interaction with GTF2H2 results in the stimulation of the 5'-->3' helicase activity (PubMed:9771713, PubMed:9852112). Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5 (PubMed:20797633). Interacts with CIAO1 and CIAO2B; the interaction WITH CIAO2B is direct (PubMed:23891004). Interacts with ATF7IP (PubMed:19106100). Interacts directly with MMS19 (PubMed:23585563). {ECO:0000269|PubMed:19106100, ECO:0000269|PubMed:20797633, ECO:0000269|PubMed:23585563, ECO:0000269|PubMed:23891004, ECO:0000269|PubMed:9771713, ECO:0000269|PubMed:9852112}.

Subunit: (Microbial infection) Interacts with Epstein-Barr virus EBNA2. {ECO:0000269|PubMed:7724549}.

Subcellular location: Nucleus {ECO:0000269|PubMed:20797633, ECO:0000269|PubMed:23585563}. Cytoplasm, cytoskeleton, spindle {ECO:0000269|PubMed:20797633}.

Ptm: ISGylated. {ECO:0000305|PubMed:16884686}.

Disease: Xeroderma pigmentosum complementation group D (XP-D) [MIM:278730]: 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. Some XP-D patients present features of Cockayne syndrome, including cachectic dwarfism, pigmentary retinopathy, ataxia, decreased nerve conduction velocities. The phenotype combining xeroderma pigmentosum and Cockayne syndrome traits is referred to as XP-CS complex. {ECO:0000269|PubMed:10447254, ECO:0000269|PubMed:11709541, ECO:0000269|PubMed:15494306, ECO:0000269|PubMed:7585650, ECO:0000269|PubMed:7825573, ECO:0000269|PubMed:7849702, ECO:0000269|PubMed:9101292}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Trichothiodystrophy 1, photosensitive (TTD1) [MIM:601675]: A form of trichothiodystrophy, an autosomal recessive disease characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The spectrum of clinical features varies from mild disease with only hair involvement to severe disease with cutaneous, neurologic and profound developmental defects. Ichthyosis, intellectual and developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections are common manifestations. There are both photosensitive and non-photosensitive forms of the disorder. TTD1 patients manifest cutaneous photosensitivity. {ECO:0000269|PubMed:11242112, ECO:0000269|PubMed:7920640, ECO:0000269|PubMed:8571952, ECO:0000269|PubMed:9195225, ECO:0000269|PubMed:9238033, ECO:0000269|PubMed:9758621}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Cerebro-oculo-facio-skeletal syndrome 2 (COFS2) [MIM:610756]: A disorder of prenatal onset characterized by microcephaly, congenital cataracts, facial dysmorphism, neurogenic arthrogryposis, growth failure and severe psychomotor retardation. COFS is considered to be part of the nucleotide-excision repair disorders spectrum that include also xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome. {ECO:0000269|PubMed:11443545}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the helicase family. RAD3/XPD subfamily. {ECO:0000305}.

Sequence caution: Sequence=AAM45142.1; Type=Erroneous gene model prediction; Evidence={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:		ATP-dependent 5'-3' DNA helicase, component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The ATP-dependent helicase activity of XPD/ERCC2 is required for DNA opening. In transcription, TFIIH has an essential role in transcription initiation. When the pre- initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. XPD/ERCC2 acts by forming a bridge between CAK and the core-TFIIH complex. Involved in the regulation of vitamin-D receptor activity. As part of the mitotic spindle-associated MMXD complex it plays a role in chromosome segregation. Might have a role in aging process and could play a causative role in the generation of skin cancers. {ECO:0000269\|PubMed:10024882, ECO:0000269\|PubMed:15494306, ECO:0000269\|PubMed:20797633, ECO:0000269\|PubMed:8413672}.


Catalytic activity:		Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.12;
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:22678361};
Cofactor:		Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883; Evidence={ECO:0000269\|PubMed:22678361}; Note=Binds 1 [4Fe-4S] cluster. {ECO:0000269\|PubMed:22678361};
Subunit:		Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK- activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription. The interaction with GTF2H2 results in the stimulation of the 5'-->3' helicase activity (PubMed:9771713, PubMed:9852112). Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5 (PubMed:20797633). Interacts with CIAO1 and CIAO2B; the interaction WITH CIAO2B is direct (PubMed:23891004). Interacts with ATF7IP (PubMed:19106100). Interacts directly with MMS19 (PubMed:23585563). {ECO:0000269\|PubMed:19106100, ECO:0000269\|PubMed:20797633, ECO:0000269\|PubMed:23585563, ECO:0000269\|PubMed:23891004, ECO:0000269\|PubMed:9771713, ECO:0000269\|PubMed:9852112}.
Subunit:		(Microbial infection) Interacts with Epstein-Barr virus EBNA2. {ECO:0000269\|PubMed:7724549}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:20797633, ECO:0000269\|PubMed:23585563}. Cytoplasm, cytoskeleton, spindle {ECO:0000269\|PubMed:20797633}.
Ptm:		ISGylated. {ECO:0000305\|PubMed:16884686}.
Disease:		Xeroderma pigmentosum complementation group D (XP-D) [MIM:278730]: 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. Some XP-D patients present features of Cockayne syndrome, including cachectic dwarfism, pigmentary retinopathy, ataxia, decreased nerve conduction velocities. The phenotype combining xeroderma pigmentosum and Cockayne syndrome traits is referred to as XP-CS complex. {ECO:0000269\|PubMed:10447254, ECO:0000269\|PubMed:11709541, ECO:0000269\|PubMed:15494306, ECO:0000269\|PubMed:7585650, ECO:0000269\|PubMed:7825573, ECO:0000269\|PubMed:7849702, ECO:0000269\|PubMed:9101292}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Trichothiodystrophy 1, photosensitive (TTD1) [MIM:601675]: A form of trichothiodystrophy, an autosomal recessive disease characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The spectrum of clinical features varies from mild disease with only hair involvement to severe disease with cutaneous, neurologic and profound developmental defects. Ichthyosis, intellectual and developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections are common manifestations. There are both photosensitive and non-photosensitive forms of the disorder. TTD1 patients manifest cutaneous photosensitivity. {ECO:0000269\|PubMed:11242112, ECO:0000269\|PubMed:7920640, ECO:0000269\|PubMed:8571952, ECO:0000269\|PubMed:9195225, ECO:0000269\|PubMed:9238033, ECO:0000269\|PubMed:9758621}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Cerebro-oculo-facio-skeletal syndrome 2 (COFS2) [MIM:610756]: A disorder of prenatal onset characterized by microcephaly, congenital cataracts, facial dysmorphism, neurogenic arthrogryposis, growth failure and severe psychomotor retardation. COFS is considered to be part of the nucleotide-excision repair disorders spectrum that include also xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome. {ECO:0000269\|PubMed:11443545}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the helicase family. RAD3/XPD subfamily. {ECO:0000305}.
Sequence caution:		Sequence=AAM45142.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};