Variations in DNA Repair Among People

Abstract

A number of inherited, cancer-prone diseases are associated with severe defects in the abilities of cells to repair damaged DNA (Setlow, 1978; Friedberg, 1985; Maher, this volume; Paterson, this volume). The diseases with the largest defects in repair are xeroderma pigmentosum (XP) and ataxia telangiectasia (AT), the former showing high levels of skin cancer as a result of sunlight irradiation and the latter, high levels of lymphoreticular cancer whose etiologic origins are unknown. The cytotoxic effects of ultraviolet radiation (UV) are much greater on XP cells than on normal cells, whereas the cytotoxic effects of X-rays are much greater on AT cells than on normal ones. It is known that XP cells are defective in one or more DNA repair pathways, but the molecular nature of the defect(s) in AT cells is not known. In XP, the skin cancer susceptibility to sunlight and the cytotoxic effects of UV on their cells in vitro show good correlations with the ability to repair UV-damaged DNA by the process of nucleotide excision. The repair defects range from approximately 20 to 95 percent. It is important to recognize that the repair defects are not 100 percent and actually average somewhere in the neighborhood of 80 percent. This 80 percent average repair defect is associated with an approximately 10⁴-fold increase in skin cancer prevalence (Setlow, 1980; Kraemer et al., 1984) and an approximately 12-fold increase in internal cancers at sites not exposed to sunlight (Kraemer et al., 1984).