Overexpression of enzymes that repair endogenous damage to DNA

A significant contribution to human mutagenesis and carcinogenesis may come from DNA damage of endogenous, rather than exogenous, origin. Efficient re pair mechanisms have evolved to cope with this. The main repair pathway inv olved in repair of endogenous damage is DNA base excision repair. In additi on, an important contribution is given by O-6-alkylguanine DNA alkyltranfer ase, that repairs specifically the miscoding base O-6-alkylguanine. In rece nt years, several attempts have been carried out to enhance the efficiency of repair of endogenous damage by overexpressing in mammalian cells single enzymatic activities. In some cases (e.g. O-6-alkylguanine DNA alkyltransfe rase or yeast AP endonuclease) this approach has been successful in improvi ng cellular protection from endogenous and exogenous mutagens, while overex pression of other enzymatic activities (e.g. alkyl N-purine glycosylase or DNA polymerase beta) were detrimental and even produced a genome instabilit y phenotype. The reasons for these different outcomes are analyzed and alte rnative enzymatic activities whose overexpression may improve the efficienc y of repair of endogenous damage in human cells are proposed.