DEFECTS IN THE DNA-REPAIR AND TRANSCRIPTION GENE ERCC2 IN THE CANCER-PRONE DISORDER XERODERMA-PIGMENTOSUM GROUP-D

Xeroderma pigmentosum (XP) is a sun-sensitive, cancer-prone genetic di sorder characterized by a defect in nucleotide excision repair. The hu man nucleotide excision repair and transcription gene ERCC2 is able to restore survival to normal levels after exposure to UV light in XP co mplementation group D cells. No enhancement of UV survival is seen in groups C, E, F, or G. XP-CS-2 cells are complemented by ERCC2, confirm ing the reassignment to group D of this combined XP/Cockayne's syndrom e patient. Nucleotide sequence analysis of the ERCC2 cDNA from five XP group D cell strains [XP6BE(SV40), XP17PV, XP102LO, A31-27 (a HeLa/XP 1O2LO hybrid), and XP-CS-2] revealed mutations predominantly affecting previously identified functional domains. The mutations include base substitutions resulting in amino acid substitutions, deletions due to splicing alterations, and defects in expression, XP6BE(SV40), XP17PV, XP102LO, and A31-27 all have one allele with an Arg683 to Trp substitu tion within the putative nuclear location signal. The genetic disorder trichothiodystrophy (which is not cancer-prone) can also result from mutations in the ERCC2 gene, some of which are the same as those found in XP-D. The various clinical presentations can be correlated with th e particular mutations found in the ERCC2 locus.