Human health risks from environmental carcinogens and genotoxic agents are modified by a range of specific gene families and polymorphisms. Progress in understanding these genes has come through genetic diseases that show increased susceptibility to environmental agents, especially ultraviolet light, and in which DNA repair mechanisms play a pivotal role. Xeroderma pigmentosum and related diseases such as Cockayne syndrome and trichothiodystrophy have been extremely informative about the role of DNA damage and excision repair in carcinogenesis, and have revealed a fundamental linkage between repair and gene transcription which may explain varied clinical symptoms involving neurological and developmental disorders. Less well understood are mechanisms by which damaged DNA is faithfully replicated by several human diseases appear to represent defects in replication fidelity and cell cycle control. These diseases which show increases susceptibility to cancer and chromosomal and genetic instability include ataxia telangiectasia, Bloom syndrome, dysplastic nevus syndrome and the XP variant. The XP variant is of especial interest because the clinical symptoms of actinic carcinogenesis and occasional cases of neurological decline are indistinguishable from excision defective XP groups A through G, yet cells show normal excision reaper. The XP variant therefore represents a linkage between the processing of DNA damage and the fidelity of DNA replication and repair whereas the other XP groups represent reductions in quantitative aspects of repair. We propose a study that will lead to cloning the XP variant and related genes and understanding its biochemistry. We have already detected increased chromosome instability that is distinctive for SV40 transformed XP variants, suggesting that the XPV gene product lies on T antigen-dependent pathways. Preliminary evidence has already provided us new insights into relationship between the XPV phenotype, the biochemical pathways of methyl transfer and genetic instability; we have cloned one gene involved in expression of increased SCES in variant cells, which is homologous to a homocysteine hydrolase and is on chromosome 1 and has alterations in its 3'utr in 2 XPV cell lines, and present strategies for identifying additional genes involved in the XPV phenotype.