Increased ultraviolet sensitivity and chromosomal instability related to p53 function in the xeroderma pigmentosum variant

The xeroderma pigmentosum (XP) variant (XPV) is a form of SP that has norma l excision repair but shows defective DNA replication after UV irradiation. In developing various transformed fibroblast cell lines from these patient s, we have found that there are significant phenotypic changes in transform ed cells that seem to correlate with inactivation of p53. After transformat ion with SV40, XPV cell lines are only slightly UV sensitive. like their pr imary counterparts, but their sensitization with caffeine and the induction of sister chromatid exchanges (SCEs) by UV irradiation are greatly enhance d. After transformation by HPV16 E7, which targets the retinoblastoma cell cycle regulatory gene, there is no change in the UV sensitivity of XPV cell s; but, when transformed by HPV16 E6 or E6 and E7 combined. there is a larg e increase in UV sensitivity and in the induction of SCEs, These changes ar e not associated with any detectable changes in the reactivation of an exte rnally irradiated luciferase expression vector, the excision of cyclobutane pyrimidine dimers from bulk DNA, or unscheduled DNA synthesis and, therefo re, do not involve excision repair. We suggest that if SCEs represent homol ogous recombination between sister chromatids, then in the absence of p53 f unction, the DNA chain arrest typical of UV-damaged XPV cells initiates str and exchange during recovery. In untransformed cells with normal p53, the p referred mode of recovery would then be replication bypass, The symptoms of elevated solar carcinogenesis in XPV patients may, therefore, he associate d with increased genomic instability in cells of the skin in which p53 is i nactivated by UV-induced mutations.