InterPro domain: IPR001945

Xeroderma pigmentosum (XP) [ 1 ] is a human autosomal recessive disease, characterised by a high incidence of sunlight-induced skin cancer. People's skin cells with this condition are hypersensitive to ultraviolet light, due to defects in the incision step of DNA excision repair. There are a minimum of seven genetic complementation groups involved in this pathway: XP-A to XP-G. XP-G is one of the most rare and phenotypically heterogeneous of XP, showing anything from slight to extreme dysfunction in DNA excision repair [ 2 , 3 ]. XP-G can be corrected by a 133 Kd nuclear protein, XPGC [ 4 ]. XPGC is an acidic protein that confers normal UV resistance in expressing cells [ 4 ]. It is a magnesium-dependent, single-strand DNA endonuclease that makes structure-specific endonucleolytic incisions in a DNA substrate containing a duplex region and single-stranded arms [ 4 , 4 ]. XPGC cleaves one strand of the duplex at the border with the single-stranded region [ 5 ].

XPG (ERCC-5) belongs to a family of proteins that includes RAD2 from Saccharomyces cerevisiae (Baker's yeast) and rad13 from Schizosaccharomyces pombe (Fission yeast), which are single-stranded DNA endonucleases [ 5 , 5 , 6 ]; mouse and human FEN-1, a structure-specific endonuclease; RAD2 from fission yeast and RAD27 from budding yeast; fission yeast exo1, a 5'-3' double-stranded DNA exonuclease that may act in a pathway that corrects mismatched base pairs; yeast DHS1, and yeast DIN7. Sequence alignment of this family of proteins reveals that similarities are largely confined to two regions. The first is located at the N-terminal extremity (N-region) and corresponds to the first 95 to 105 amino acids. The second region is internal (I-region) and found towards the C terminus; it spans about 140 residues and contains a highly conserved core of 27 amino acids that includes a conserved pentapeptide (E-A-[DE]-A-[QS]). It is possible that the conserved acidic residues are involved in the catalytic mechanism of DNA excision repair in XPG. The amino acids linking the N- and I-regions are not conserved.

The XP group D gene product (XPD) is a helicase that is required for nucleotide excision repair, and is also one of the components of basal transcription factor TFIIH [ 7 , 8 ]. DNA repair defects in the XPD group are associated with the clinical features of XP and trichothiodystrophy (TTD), which is characterised by sulphur-deficient brittle hair and a variety of other associated abnormalities, but no skin cancer [ 9 ].

XPD belongs to a family of ATP-dependent helicases that are characterised by a 'D-E-A-H' motif [ 9 ]. This resembles the 'D-E-A-D-box' of other known helicases, which represents a special version of the B motif of ATP-binding proteins. In XPD, His replaces the second Asp.

1. Xeroderma pigmentosum and nucleotide excision repair of DNA. Trends Biochem. Sci. 19, 83-6
2. Evolutionary conservation of excision repair in Schizosaccharomyces pombe: evidence for a family of sequences related to the Saccharomyces cerevisiae RAD2 gene. Nucleic Acids Res. 21, 1345-9
3. Isolation of active recombinant XPG protein, a human DNA repair endonuclease. J. Biol. Chem. 269, 15965-8
4. XPG endonuclease makes the 3' incision in human DNA nucleotide excision repair. Nature 371, 432-5
5. Yeast excision repair gene RAD2 encodes a single-stranded DNA endonuclease. Nature 366, 365-8
6. The crystal structure of human XPG, the xeroderma pigmentosum group G endonuclease, provides insight into nucleotide excision DNA repair. Nucleic Acids Res 48, 9943-9958
7. Mutations in the XPD gene leading to xeroderma pigmentosum symptoms. Hum. Mutat. 9, 322-31
8. Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy. Nat. Genet. 7, 189-94
9. The RAD3 gene is a member of the DEAH family RNA helicase-like protein. Nucleic Acids Res. 19, 6331