Regulation of eukaryotic abasic endonucleases and their role in genetic stability.

Abstract

Abasic (AP) sites in DNA arise from spontaneous reactions or the action of DNA glycosylases and represent a loss of genetic information. The AP sites can be mutagenic or cytotoxic, and their repair is initiated by class II AP endonucleases, which incise immediately 5' to AP sites. The main enzyme of S. cerevisiae. Apn1, provides cellular resistance to oxidants (e.g., H2O2) or alkylating agents, and limits the spontaneous mutation rate. AP endonucleases from other species can replace Apn1 function in yeast to different extents. We studied the main human enzyme, Ape, with respect to its incision specificity in vitro and the expression of the APE gene in vivo. The results suggest that Ape evolved to act preferentially on AP sites compared to deoxyribose fragments located at oxidative strand breaks and that the incision modes of Ape and Apn1 may be fundamentally different. We also defined the functional APE promoter, and showed that APE expression is transiently downregulated during the regeneration of epidermis after wounding. This latter effect may lead to a window of vulnerability for DNA damage and perhaps mutagenesis during the healing of epidermal and other wounds. Such unexpected effects on the expression of DNA repair enzymes need to be taken into account in analyzing the susceptibility of different tissues to carcinogens.