The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides

Abstract The DNA polymerase module of the Pfprex enzyme (PfpPol) is responsible for duplication of the genome of the apicoplast organelle in the malaria parasite. We show that PfpPol can misincorporate oxidized nucleotides such as 8oxodGTP opposite dA. This event gives rise to transversion mutations...

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Autores principales:	Minakshi Sharma, Naveen Narayanan, Deepak T. Nair
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ec5352a575ec49d0b5c184c73eeb1cfc
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spelling	oai:doaj.org-article:ec5352a575ec49d0b5c184c73eeb1cfc2021-12-02T15:39:50ZThe proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides10.1038/s41598-020-67853-22045-2322https://doaj.org/article/ec5352a575ec49d0b5c184c73eeb1cfc2020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-67853-2https://doaj.org/toc/2045-2322Abstract The DNA polymerase module of the Pfprex enzyme (PfpPol) is responsible for duplication of the genome of the apicoplast organelle in the malaria parasite. We show that PfpPol can misincorporate oxidized nucleotides such as 8oxodGTP opposite dA. This event gives rise to transversion mutations that are known to lead to adverse physiological outcomes. The apicoplast genome is particularly vulnerable to the harmful effects of 8oxodGTP due to very high AT content (~ 87%). We show that the proofreading activity of PfpPol has the unique ability to remove the oxidized nucleotide from the primer terminus. Due to this property, the proofreading domain of PfpPol is able to prevent mutagenesis of the AT-rich apicoplast genome and neutralize the deleterious genotoxic effects of ROS generated in the apicoplast due to normal metabolic processes. The proofreading activity of the Pfprex enzyme may, therefore, represent an attractive target for therapeutic intervention. Also, a survey of DNA repair pathways shows that the observed property of Pfprex constitutes a novel form of dynamic error correction wherein the repair of promutagenic damaged nucleotides is concomitant with DNA replication.Minakshi SharmaNaveen NarayananDeepak T. NairNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Minakshi Sharma Naveen Narayanan Deepak T. Nair The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides
description	Abstract The DNA polymerase module of the Pfprex enzyme (PfpPol) is responsible for duplication of the genome of the apicoplast organelle in the malaria parasite. We show that PfpPol can misincorporate oxidized nucleotides such as 8oxodGTP opposite dA. This event gives rise to transversion mutations that are known to lead to adverse physiological outcomes. The apicoplast genome is particularly vulnerable to the harmful effects of 8oxodGTP due to very high AT content (~ 87%). We show that the proofreading activity of PfpPol has the unique ability to remove the oxidized nucleotide from the primer terminus. Due to this property, the proofreading domain of PfpPol is able to prevent mutagenesis of the AT-rich apicoplast genome and neutralize the deleterious genotoxic effects of ROS generated in the apicoplast due to normal metabolic processes. The proofreading activity of the Pfprex enzyme may, therefore, represent an attractive target for therapeutic intervention. Also, a survey of DNA repair pathways shows that the observed property of Pfprex constitutes a novel form of dynamic error correction wherein the repair of promutagenic damaged nucleotides is concomitant with DNA replication.
format	article
author	Minakshi Sharma Naveen Narayanan Deepak T. Nair
author_facet	Minakshi Sharma Naveen Narayanan Deepak T. Nair
author_sort	Minakshi Sharma
title	The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides
title_short	The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides
title_full	The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides
title_fullStr	The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides
title_full_unstemmed	The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides
title_sort	proofreading activity of pfprex from plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/ec5352a575ec49d0b5c184c73eeb1cfc
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The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides

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