Gene prophylaxis of endogenous DNA damage

A significant contribution to human mutagenesis and carcinogenesis may come from DNA damage of endogenous, rather than exogenous, origin. Efficient repair mechanisms have evolved to cope with it. The major pathway involved in DNA repair of endogenous damage is DNA base excision repair (BER). In addition, an important contribution is given by O⁶ alkylguanine DNA alkyltranferase, that repairs specifically the miscoding base O⁶ alkylguanine. BER is rather efficient in human cells but a certain amount of endogenous damage inevitably escapes mending and likely contributes to human carcinogenesis. Several attempts have been carried out to enhance the efficiency of repair of endogenous DNA damage by overexpressing in mammalian cells single enzymatic activities. In some cases (e.g. formamidopyrimidine DNA glycosylase or O⁶ alkylguanine DNA alkyltransferase) this approach turned out successful in improving cellular protection from endogenous and exogenous mutagens while overexpression of other enzymatic activities (e.g alkyl N-purine DNA glycosylase or DNA polymerase β) was detrimental and even produced a genome instability phenotype. Prophylaxis of endogenous DNA damage and mutation could be achieved in at-risk individuals by expression of appropriate DNA repair genes. Currently available vehicles for this peculiar type of gene therapy are surveyed.