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

Nature Structural & Molecular Biology
Young-Sam LeeWei Yang

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 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.

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Citations

Jun 7, 2016·DNA Repair·Richard D Wood, Sylvie Doublié
Oct 16, 2016·Chemical Research in Toxicology·A S Prakasha Gowda, Thomas E Spratt
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Oct 3, 2018·Proceedings of the National Academy of Sciences of the United States of America·Peter J WengWei Yang
May 13, 2015·The Journal of Biological Chemistry·A S Prakasha GowdaThomas E Spratt
Jul 11, 2018·Proceedings of the National Academy of Sciences of the United States of America·Peng He, Wei Yang
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Apr 21, 2021·Nucleic Acids Research·Jie YangXiaodong Cheng
Jun 6, 2021·Proceedings of the National Academy of Sciences of the United States of America·Mark T GregoryWei Yang
Feb 10, 2018·Journal of the American Chemical Society·Vito GennaMarco De Vivo

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Software Mentioned

PHENIX
PyMol
ImageQuant TL
HKL2000
COOT

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