Polymerase eta deficiency in the xeroderma pigmentosum variant uncovers anoverlap between the S phase checkpoint and double-strand break repair

The xeroderma pigmentosum variant (XPV) is a genetic disease involving high levels of solar-induced cancer that has normal excision repair but shows d efective DNA replication after UV irradiation because of mutations in the d amage-specific polymerase hRAD30. We previously found that the induction of sister chromatid exchanges by UV irradiation was greatly enhanced in trans formed XPV cells, indicating the activation of a recombination pathway. We now have identified that XPV cells make use of a homologous recombination p athway involving the hMre11/hRad50/Nbs1 protein complex, but not the Rad51 recombination pathway. The hMre11 complexes form at arrested replication fo rks, in association with proliferating cell nuclear antigen. In x-ray-damag ed cells, in contrast, there is no association between hMre11 and prolifera ting cell nuclear antigen. This recombination pathway assumes greater impor tance in transformed XPV cells that lack a functional p53 pathway and can b e detected at lower frequencies in excision-defective XPA fibroblasts and n ormal cells, DNA replication arrest after UV damage, and the associated S p hase checkpoint is therefore a complex process that can recruit a recombina tion pathway that has a primary role in repair of double-strand breaks from x-rays, The symptoms of elevated solar carcinogenesis in XPV patients ther efore may be associated with increased genomic rearrangements that result f rom double-strand breakage and rejoining in cells of the skin in which p53 is inactivated by UV-induced mutations.