How a homolog of high-fidelity replicases conducts mutagenic DNA synthesis.

ABSTRACT: All DNA replicases achieve high fidelity by a conserved mechanism, but each translesion polymerase carries out mutagenic DNA synthesis in its own way. Here we report crystal structures of human DNA polymerase ? (Pol ?), which is homologous to high-fidelity replicases yet is error prone. Instead of a simple open-to-closed movement of the O helix upon binding of a correct incoming nucleotide, Pol ? has a different open state and requires the finger domain to swing sideways and undergo both opening and closing motions to accommodate the nascent base pair. A single-amino acid substitution in the O helix of the finger domain improves the fidelity of Pol ? nearly ten-fold. A unique cavity and the flexibility of the thumb domain allow Pol ? to generate and accommodate a looped-out primer strand. Primer loop-out may be a mechanism for DNA trinucloetide-repeat expansion.

SUBMITTER: Lee YS 

PROVIDER: S-EPMC4469489 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature