Mycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP

PLoS Pathogens
Liang-Dong LyuGuo-Ping Zhao

Abstract

Generation of reactive oxygen species and reactive nitrogen species in phagocytes is an important innate immune response mechanism to eliminate microbial pathogens. It is known that deoxynucleotides (dNTPs), the precursor nucleotides to DNA synthesis, are one group of the significant targets for these oxidants and incorporation of oxidized dNTPs into genomic DNA may cause mutations and even cell death. Here we show that the mycobacterial dNTP pyrophosphohydrolase MazG safeguards the bacilli genome by degrading 5-OH-dCTP, thereby, preventing it from incorporation into DNA. Deletion of the (d)NTP pyrophosphohydrolase-encoding mazG in mycobacteria leads to a mutator phenotype both under oxidative stress and in the stationary phase of growth, resulting in increased CG to TA mutations. Biochemical analyses demonstrate that mycobacterial MazG can efficiently hydrolyze 5-OH-dCTP, an oxidized nucleotide that induces CG to TA mutation upon incorporation by polymerase. Moreover, chemical genetic analyses show that direct incorporation of 5-OH-dCTP into mazG-null mutant strain of Mycobacterium smegmatis (Msm) leads to a dose-dependent mutagenesis phenotype, indicating that 5-OH-dCTP is a natural substrate of mycobacterial MazG. Furthermor...Continue Reading

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Citations

Jul 24, 2014·The FEBS Journal·Gergely N NagyBeáta G Vértessy
Feb 16, 2018·Proceedings of the National Academy of Sciences of the United States of America·Aviram Rasouly, Evgeny Nudler
Feb 1, 2018·Proceedings of the National Academy of Sciences of the United States of America·Xiao-Yong FanLiang-Dong Lyu
Mar 22, 2018·Emerging Microbes & Infections·Hua YangBaoxue Ge
Jun 4, 2016·Journal of Basic Microbiology·Bhaskar Chandra Mohan RamisettyDimpy Ghosh
Nov 30, 2018·Environment International·Ye ZhangJianmin Chen

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Methods Mentioned

BETA
deamination
PCR
genotyping

Software Mentioned

GraphPad Prism
BioEdit
Image Pro Plus

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