The A-Rule and Deletion Formation During Abasic and Oxidized Abasic Site Bypass by DNA Polymerase ?.

ABSTRACT: DNA polymerase ? (Pol ?) is implicated in various cellular processes including double-strand break repair and apurinic/apyrimidinic site bypass. Because Pol ? expression correlates with poor cancer prognosis, the ability of Pol ? to bypass the C4'-oxidized abasic site (C4-AP) and 2-deoxyribonolactone (L), which are generated by cytotoxic agents, is of interest. Translesion synthesis and subsequent extension by Pol ? past C4-AP or L and an abasic site (AP) or its tetrahydrofuran analogue (F) was examined. Pol ? conducts translesion synthesis on templates containing AP and F with similar efficiencies and follows the "A-rule," inserting nucleotides in the order A > G > T. Translesion synthesis on templates containing C4-AP and L is less efficient than AP and F, and the preference for A insertion is reduced for L and absent for C4-AP. Extension past all abasic lesions (AP, F, C4-AP, and L) was significantly less efficient than translesion synthesis and yielded deletions caused by the base one or two nucleotides downstream from the lesion being used as a template, with the latter being favored. These results suggest that bypass of abasic lesions by Pol ? is highly mutagenic.

SUBMITTER: Laverty DJ 

PROVIDER: S-EPMC5499511 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature