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

2015; Nature Portfolio; Volume: 22; Issue: 4 Linguagem: Inglês

10.1038/nsmb.2985

1545-9993

Young‐Sam Lee, Yang Gao, Wei Yang,

Bacterial Genetics and Biotechnology

Though related to high-fidelity replicases, DNA Pol ν performs mutagenic DNA synthesis. These properties are now explained by structural and biochemistry analyses of human DNA Pol ν revealing conformational changes involving the finger and thumb domains. 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 ν (Pol ν), 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 ν 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 ν nearly ten-fold. A unique cavity and the flexibility of the thumb domain allow Pol ν to generate and accommodate a looped-out primer strand. Primer loop-out may be a mechanism for DNA trinucloetide-repeat expansion.