Critical amino acids in human DNA polymerases eta and kappa involved in erroneous incorporation of oxidized nucleotides.

Nucleic Acids Research
Atsushi KatafuchiTakehiko Nohmi

Abstract

Oxidized DNA precursors can cause mutagenesis and carcinogenesis when they are incorporated into the genome. Some human Y-family DNA polymerases (Pols) can effectively incorporate 8-oxo-dGTP, an oxidized form of dGTP, into a position opposite a template dA. This inappropriate G:A pairing may lead to transversions of A to C. To gain insight into the mechanisms underlying erroneous nucleotide incorporation, we changed amino acids in human Poleta and Polkappa proteins that might modulate their specificity for incorporating 8-oxo-dGTP into DNA. We found that Arg61 in Poleta was crucial for erroneous nucleotide incorporation. When Arg61 was substituted with lysine (R61K), the ratio of pairing of dA to 8-oxo-dGTP compared to pairing of dC was reduced from 660:1 (wild-type Poleta) to 7 : 1 (R61K). Similarly, Tyr112 in Polkappa was crucial for erroneous nucleotide incorporation. When Tyr112 was substituted with alanine (Y112A), the ratio of pairing was reduced from 11: 1 (wild-type Polkappa) to almost 1: 1 (Y112A). Interestingly, substitution at the corresponding position in Poleta, i.e. Phe18 to alanine, did not alter the specificity. These results suggested that amino acids at distinct positions in the active sites of Poleta and Polk...Continue Reading

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Citations

Jan 14, 2011·Biochemistry·Jessica A Brown, Zucai Suo
Aug 5, 2015·Proceedings of the National Academy of Sciences of the United States of America·Yih-Wen ChenKai-ming Chou
Sep 25, 2012·Biochimie·Nina G DolinnayaTatiana S Oretskaya
Jun 18, 2016·DNA Repair·Sean G RuddThomas Helleday
Nov 2, 2016·Nucleic Acids Research·Tatiana KentRichard T Pomerantz
Jul 5, 2018·Critical Reviews in Biochemistry and Molecular Biology·Alexandra Vaisman, Roger Woodgate
Mar 28, 2020·The Journal of Biological Chemistry·Pratibha P Ghodke, F Peter Guengerich
Feb 10, 2018·Journal of the American Chemical Society·Vito GennaMarco De Vivo

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Methods Mentioned

BETA
electrophoresis

Software Mentioned

Molecular Operating Environment ( MOE
Quantity One
SigmaPlot

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