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

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 the...

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Autores principales:	Liang-Dong Lyu, Bi-Kui Tang, Xiao-Yong Fan, Hui Ma, Guo-Ping Zhao
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e9175808bc0549d0bee139b2c16ef4c8
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spelling	oai:doaj.org-article:e9175808bc0549d0bee139b2c16ef4c82021-11-18T06:07:16ZMycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP.1553-73661553-737410.1371/journal.ppat.1003814https://doaj.org/article/e9175808bc0549d0bee139b2c16ef4c82013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24339782/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Generation 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. Furthermore, deletion of mazG in Mycobacterium tuberculosis (Mtb) leads to reduced survival in activated macrophages and in the spleen of infected mice. This study not only characterizes the mycobacterial MazG as a novel pyrimidine-specific housecleaning enzyme that prevents CG to TA mutation by degrading 5-OH-dCTP but also reveals a genome-safeguarding mechanism for survival of Mtb in vivo.Liang-Dong LyuBi-Kui TangXiao-Yong FanHui MaGuo-Ping ZhaoPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 12, p e1003814 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Liang-Dong Lyu Bi-Kui Tang Xiao-Yong Fan Hui Ma Guo-Ping Zhao Mycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP.
description	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. Furthermore, deletion of mazG in Mycobacterium tuberculosis (Mtb) leads to reduced survival in activated macrophages and in the spleen of infected mice. This study not only characterizes the mycobacterial MazG as a novel pyrimidine-specific housecleaning enzyme that prevents CG to TA mutation by degrading 5-OH-dCTP but also reveals a genome-safeguarding mechanism for survival of Mtb in vivo.
format	article
author	Liang-Dong Lyu Bi-Kui Tang Xiao-Yong Fan Hui Ma Guo-Ping Zhao
author_facet	Liang-Dong Lyu Bi-Kui Tang Xiao-Yong Fan Hui Ma Guo-Ping Zhao
author_sort	Liang-Dong Lyu
title	Mycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP.
title_short	Mycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP.
title_full	Mycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP.
title_fullStr	Mycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP.
title_full_unstemmed	Mycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP.
title_sort	mycobacterial mazg safeguards genetic stability via housecleaning of 5-oh-dctp.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/e9175808bc0549d0bee139b2c16ef4c8
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Mycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP.

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