Molecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG1

The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pa...

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Autores principales:	Tao Jiang, Antonio Monari, Elise Dumont, Emmanuelle Bignon
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	DNA repair clustered DNA lesions DNA glycosylases molecular dynamics Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/2a0b18d57c224c66949df87606a6d5e6
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spelling	oai:doaj.org-article:2a0b18d57c224c66949df87606a6d5e62021-11-11T18:28:26ZMolecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG110.3390/molecules262164651420-3049https://doaj.org/article/2a0b18d57c224c66949df87606a6d5e62021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6465https://doaj.org/toc/1420-3049The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, which ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features, and repair have been matters of extensive research; more recently, this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">μ</mi></semantics></math></inline-formula>s-range molecular dynamics simulations and machine-learning-based postanalysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple-lesion site with a mismatch in 5<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mo>′</mo></msup></semantics></math></inline-formula> or 3<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mo>′</mo></msup></semantics></math></inline-formula>. We delineate the stiffening of the DNA–protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mo>′</mo></msup></semantics></math></inline-formula> mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion.Tao JiangAntonio MonariElise DumontEmmanuelle BignonMDPI AGarticleDNA repairclustered DNA lesionsDNA glycosylasesmolecular dynamicsOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6465, p 6465 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA repair clustered DNA lesions DNA glycosylases molecular dynamics Organic chemistry QD241-441
spellingShingle	DNA repair clustered DNA lesions DNA glycosylases molecular dynamics Organic chemistry QD241-441 Tao Jiang Antonio Monari Elise Dumont Emmanuelle Bignon Molecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG1
description	The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, which ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features, and repair have been matters of extensive research; more recently, this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">μ</mi></semantics></math></inline-formula>s-range molecular dynamics simulations and machine-learning-based postanalysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple-lesion site with a mismatch in 5<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mo>′</mo></msup></semantics></math></inline-formula> or 3<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mo>′</mo></msup></semantics></math></inline-formula>. We delineate the stiffening of the DNA–protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mrow></mrow><mo>′</mo></msup></semantics></math></inline-formula> mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion.
format	article
author	Tao Jiang Antonio Monari Elise Dumont Emmanuelle Bignon
author_facet	Tao Jiang Antonio Monari Elise Dumont Emmanuelle Bignon
author_sort	Tao Jiang
title	Molecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG1
title_short	Molecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG1
title_full	Molecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG1
title_fullStr	Molecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG1
title_full_unstemmed	Molecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG1
title_sort	molecular mechanisms associated with clustered lesion-induced impairment of 8-oxog recognition by the human glycosylase ogg1
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2a0b18d57c224c66949df87606a6d5e6
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Molecular Mechanisms Associated with Clustered Lesion-Induced Impairment of 8-oxoG Recognition by the Human Glycosylase OGG1

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