A mechanism for the exclusion of low-fidelity human Y-family DNA polymerases from base excision repair

Abstract

The human Y-family DNA polymerases, Polι, Polη, and Polκ, function in promoting replication through DNA lesions. However, because of their low fidelity, any involvement of these polymerases in DNA synthesis during base excision repair (BER) would be highly mutagenic. Mechanisms, therefore, must exist to exclude their participation in BER. Here, we show that although Polι, Polη, and Polκ are all able to form a covalent Schiff base intermediate with the 5′-deoxyribose phosphate (5′-dRP) residue that results from the incision of DNA at an abasic site by an AP endonuclease, they all lack the ability for the subsequent catalytic removal of the 5′-dRP group. Instead, the covalent trapping of these polymerases by the 5′-dRP residue inhibits their DNA synthetic activity during BER. The unprecedented ability of these polymerases for robust Schiff base formation without the release of the 5′-dRP product provides a means of preventing their participation in the DNA synthetic step of BER, thereby avoiding the high incidence of mutagenesis and carcinogenesis that would otherwise occur.