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OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions

8-oxoguanine DNA glycosylase (OGG1) is the main DNA glycosylase responsible for the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from duplex DNA to initiate base excision repair. This glycosylase activity is relevant in many pathological conditions including cancer, inflammation, and neurodegenerat...

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Autores principales: Hanna, Bishoy M. F., Helleday, Thomas, Mortusewicz, Oliver
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693665/
https://www.ncbi.nlm.nih.gov/pubmed/33114607
http://dx.doi.org/10.3390/biom10111483
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author Hanna, Bishoy M. F.
Helleday, Thomas
Mortusewicz, Oliver
author_facet Hanna, Bishoy M. F.
Helleday, Thomas
Mortusewicz, Oliver
author_sort Hanna, Bishoy M. F.
collection PubMed
description 8-oxoguanine DNA glycosylase (OGG1) is the main DNA glycosylase responsible for the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from duplex DNA to initiate base excision repair. This glycosylase activity is relevant in many pathological conditions including cancer, inflammation, and neurodegenerative diseases. To have a better understanding of the role of OGG1, we previously reported TH5487, a potent active site inhibitor of OGG1. Here, we further investigate the consequences of inhibiting OGG1 with TH5487. TH5487 treatment induces accumulation of genomic 8-oxoG lesions. Furthermore, it impairs the chromatin binding of OGG1 and results in lower recruitment of OGG1 to regions of DNA damage. Inhibiting OGG1 with TH5487 interferes with OGG1′s incision activity, resulting in fewer DNA double-strand breaks in cells exposed to oxidative stress. This study validates TH5487 as a potent OGG1 inhibitor that prevents the repair of 8-oxoG and alters OGG1–chromatin dynamics and OGG1′s recruitment kinetics.
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spelling pubmed-76936652020-11-28 OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions Hanna, Bishoy M. F. Helleday, Thomas Mortusewicz, Oliver Biomolecules Article 8-oxoguanine DNA glycosylase (OGG1) is the main DNA glycosylase responsible for the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from duplex DNA to initiate base excision repair. This glycosylase activity is relevant in many pathological conditions including cancer, inflammation, and neurodegenerative diseases. To have a better understanding of the role of OGG1, we previously reported TH5487, a potent active site inhibitor of OGG1. Here, we further investigate the consequences of inhibiting OGG1 with TH5487. TH5487 treatment induces accumulation of genomic 8-oxoG lesions. Furthermore, it impairs the chromatin binding of OGG1 and results in lower recruitment of OGG1 to regions of DNA damage. Inhibiting OGG1 with TH5487 interferes with OGG1′s incision activity, resulting in fewer DNA double-strand breaks in cells exposed to oxidative stress. This study validates TH5487 as a potent OGG1 inhibitor that prevents the repair of 8-oxoG and alters OGG1–chromatin dynamics and OGG1′s recruitment kinetics. MDPI 2020-10-26 /pmc/articles/PMC7693665/ /pubmed/33114607 http://dx.doi.org/10.3390/biom10111483 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hanna, Bishoy M. F.
Helleday, Thomas
Mortusewicz, Oliver
OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions
title OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions
title_full OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions
title_fullStr OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions
title_full_unstemmed OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions
title_short OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions
title_sort ogg1 inhibitor th5487 alters ogg1 chromatin dynamics and prevents incisions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693665/
https://www.ncbi.nlm.nih.gov/pubmed/33114607
http://dx.doi.org/10.3390/biom10111483
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