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Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition

Thymine DNA glycosylase (TDG), as a repair enzyme, plays essential roles in maintaining the genome integrity by correcting several mismatched/damaged nucleobases. TDG acquires an efficient strategy to search for the lesions among a vast number of cognate base pairs. Currently, atomic-level details o...

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Autores principales: Tian, Jiaqi, Wang, Lingyan, Da, Lin-Tai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897493/
https://www.ncbi.nlm.nih.gov/pubmed/33469643
http://dx.doi.org/10.1093/nar/gkaa1252
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author Tian, Jiaqi
Wang, Lingyan
Da, Lin-Tai
author_facet Tian, Jiaqi
Wang, Lingyan
Da, Lin-Tai
author_sort Tian, Jiaqi
collection PubMed
description Thymine DNA glycosylase (TDG), as a repair enzyme, plays essential roles in maintaining the genome integrity by correcting several mismatched/damaged nucleobases. TDG acquires an efficient strategy to search for the lesions among a vast number of cognate base pairs. Currently, atomic-level details of how TDG translocates along DNA as it approaches the lesion site and the molecular mechanisms of the interplay between TDG and DNA are still elusive. Here, by constructing the Markov state model based on hundreds of molecular dynamics simulations with an integrated simulation time of ∼25 μs, we reveal the rotation-coupled sliding dynamics of TDG along a 9 bp DNA segment containing one G·T mispair. We find that TDG translocates along DNA at a relatively faster rate when distant from the lesion site, but slows down as it approaches the target, accompanied by deeply penetrating into the minor-groove, opening up the mismatched base pair and significantly sculpturing the DNA shape. Moreover, the electrostatic interactions between TDG and DNA are found to be critical for mediating the TDG translocation. Notably, several uncharacterized TDG residues are identified to take part in regulating the conformational switches of TDG occurred in the site-transfer process, which warrants further experimental validations.
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spelling pubmed-78974932021-02-25 Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition Tian, Jiaqi Wang, Lingyan Da, Lin-Tai Nucleic Acids Res Computational Biology Thymine DNA glycosylase (TDG), as a repair enzyme, plays essential roles in maintaining the genome integrity by correcting several mismatched/damaged nucleobases. TDG acquires an efficient strategy to search for the lesions among a vast number of cognate base pairs. Currently, atomic-level details of how TDG translocates along DNA as it approaches the lesion site and the molecular mechanisms of the interplay between TDG and DNA are still elusive. Here, by constructing the Markov state model based on hundreds of molecular dynamics simulations with an integrated simulation time of ∼25 μs, we reveal the rotation-coupled sliding dynamics of TDG along a 9 bp DNA segment containing one G·T mispair. We find that TDG translocates along DNA at a relatively faster rate when distant from the lesion site, but slows down as it approaches the target, accompanied by deeply penetrating into the minor-groove, opening up the mismatched base pair and significantly sculpturing the DNA shape. Moreover, the electrostatic interactions between TDG and DNA are found to be critical for mediating the TDG translocation. Notably, several uncharacterized TDG residues are identified to take part in regulating the conformational switches of TDG occurred in the site-transfer process, which warrants further experimental validations. Oxford University Press 2021-01-19 /pmc/articles/PMC7897493/ /pubmed/33469643 http://dx.doi.org/10.1093/nar/gkaa1252 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Computational Biology
Tian, Jiaqi
Wang, Lingyan
Da, Lin-Tai
Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition
title Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition
title_full Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition
title_fullStr Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition
title_full_unstemmed Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition
title_short Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition
title_sort atomic resolution of short-range sliding dynamics of thymine dna glycosylase along dna minor-groove for lesion recognition
topic Computational Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897493/
https://www.ncbi.nlm.nih.gov/pubmed/33469643
http://dx.doi.org/10.1093/nar/gkaa1252
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