Keynote: Past, present, and future aspects of base excision repair

Abstract

Covalent alterations of DNA bases, which may have promutagenic or cytotoxic effects, are major consequences of endogenous DNA damage caused by hydrolysis, reactive oxygen species, and several metabolites and coenzymes. A common strategy for initiation of DNA base excision repair (BER) involves a DNA glycosylase that binds the altered deoxynucleoside in an extrahelical position and catalyzes cleavage of the base-sugar bond. Subsequently, an AP endonuclease or AP lyase activity incises the abasic site, followed by short-patch gap-filling, excision of the base-free sugar-phosphate residue, and ligation. The initial work that resulted in the discovery of DNA glycosylases and AP endonucleases is briefly reviewed. In recent years, it has been shown that the latter steps of the BER pathway differ greatly between mammalian cells and microorganisms such as yeast and bacteria. Three distinct subpathways of BER occur in mammalian cells, and these have been individually reconstituted with purified enzymes. Gene knockout mice are now revealing specific roles and backup mechanisms for repair functions in murine cells, and the results in general are also applicable to human cells. Future developments in the field of base excision repair include definition by proteomics of all factors involved in handling many different types of DNA lesions, clarification of mechanisms of repair of chromatin at a high level of accuracy, manifestation of repair proteins as drug targets for cellular sensitization to ionizing radiation and anticancer medicines, and elucidation of cross-talk between the base excision repair factors and other cellular proteins involved in a variety of stress responses.