1. TANAKA, K. AND WOOD, R.D.
Xeroderma pigmentosum and nucleotide excision-repair of DNA.
TRENDS BIOCHEM.SCI. 19 83-86 (1994).
2. SCHERLY, D., NOUSPIKEL, T., CORLET, J., UCLA, C., BAIROCH, A.
AND CLARKSON, S.G.
Complementation of the DNA repair defect in xeroderma pigmentosum
group G cells by a human cDNA related to yeast RAD2.
NATURE 363 182-185 (1993).
3. CARR, A.M., SHELDRICK, K.S., MURRAY, J.M., AL-HARITHY, R., WATTS, F.Z.
AND LEHMANN, A.R.
Evolutionary conservation of excision repair in Schizosaccharomyces pombe -
evidence for a family of sequences related to the Saccharomyces cerevisiae
NUCLEIC ACIDS RES. 21 1345-1349 (1993).
4. O'DONOVAN, A., SCHERLY, D., CLARKSON, S.G. AND WOOD, R.D.
Isolation of active recombinant XPG protein, a human DNA repair
J.BIOL.CHEM. 269 15965-15968 (1994).
5. O'DONOVAN, A., DAVIES, A.A., MOGGS, J.G., WEST, S.C. AND WOOD, R.D.
XPG endonuclease makes the 3' incision in human DNA nucleotide excision
NATURE 371 432-435 (1994).
6. HABRAKEN, Y., SUNG, P., PRAKASH, L. AND PRAKASH, S.
Yeast excision repair gene RAD2 encodes a single-stranded DNA endonuclease.
NATURE 366 365-368 (1993).
Defects in DNA repair proteins can give rise, in humans, to the autosomal
recessive disorders xeroderma pigmentosum (XP) and Cockayne's syndrome [1,2].
XP is characterised by a high incidence of sunlight-induced skin cancer,
the effect of skin-cell hypersensitivity to UV resulting from defects in
the nucleotide excision pathway. Seven XP complementation groups have
been identified: 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 [3,4].
XP-G can be corrected by a 133 Kd nuclear protein, XPGC . XPGC is an
acidic protein that confers normal UV resistance in expressing cells .
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 [4,5]. XPGC cleaves one strand of
the duplex at the border with the single-stranded region .
XPG belongs to a family of proteins that includes RAD2 from budding yeast
and rad13 from fission yeast, which are single-stranded DNA endonucleases
[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 analysis reveals that similarities within the family are largely
confined to two well-conserved domains, the first of which is located at
the N-terminal extremity (the N-region), the second lying towards the
C-terminus (the I-region). The I-region contains a perfectly conserved
hexapeptide, EAEAQC, the Glu and Cys residues of which may be involved in
the excision repair mechanism.
XPGRADSUPER is a 5-element fingerprint that provides a signature for the
XPG/RAD superfamily. The fingerprint was derived from an initial alignment
of 17 sequences: the motifs were drawn from short conserved regions within
the N- and C-terminal portions of the alignment - motifs 1 and 2 lie within
the N-domain, motif 2 including the region encoded by PROSITE pattern XPG_1
(PS00841); and motifs 3-5 lie in the I domain, motif 3 including the region
encoded by PROSITE pattern XPG_2 (PS00842), which contains a putative
catalytic core pentapeptide. Two iterations on OWL30.0 were required to
reach convergence, at which point a true set comprising 23 sequences was
identified. Several partial matches were also found: CELT12A25 is a
C.elegans sequence that fails to match the first 2 motifs; and YA31_SCHPO,
YEN1_YEAST and SCU13615 are yeast proteins that match only 2 motifs.
An update on SPTR37_9f identified a true set of 32 sequences, and 2