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Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair
Reactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is requir...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379156/ https://www.ncbi.nlm.nih.gov/pubmed/34417448 http://dx.doi.org/10.1038/s41467-021-24486-x |
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author | Jamsen, Joonas A. Sassa, Akira Perera, Lalith Shock, David D. Beard, William A. Wilson, Samuel H. |
author_facet | Jamsen, Joonas A. Sassa, Akira Perera, Lalith Shock, David D. Beard, William A. Wilson, Samuel H. |
author_sort | Jamsen, Joonas A. |
collection | PubMed |
description | Reactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is required for successful NHEJ in vivo. We previously showed that pol μ lacks discrimination against oxidized dGTP (8-oxo-dGTP), that can lead to mutagenesis, cancer, aging and human disease. Here we reveal the structural basis for proficient oxidized ribonucleotide (8-oxo-rGTP) incorporation during DSB repair by pol μ. Time-lapse crystallography snapshots of structural intermediates during nucleotide insertion along with computational simulations reveal substrate, metal and side chain dynamics, that allow oxidized ribonucleotides to escape polymerase discrimination checkpoints. Abundant nucleotide pools, combined with inefficient sanitization and repair, implicate pol μ mediated oxidized ribonucleotide insertion as an emerging source of widespread persistent mutagenesis and genomic instability. |
format | Online Article Text |
id | pubmed-8379156 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-83791562021-09-22 Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair Jamsen, Joonas A. Sassa, Akira Perera, Lalith Shock, David D. Beard, William A. Wilson, Samuel H. Nat Commun Article Reactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is required for successful NHEJ in vivo. We previously showed that pol μ lacks discrimination against oxidized dGTP (8-oxo-dGTP), that can lead to mutagenesis, cancer, aging and human disease. Here we reveal the structural basis for proficient oxidized ribonucleotide (8-oxo-rGTP) incorporation during DSB repair by pol μ. Time-lapse crystallography snapshots of structural intermediates during nucleotide insertion along with computational simulations reveal substrate, metal and side chain dynamics, that allow oxidized ribonucleotides to escape polymerase discrimination checkpoints. Abundant nucleotide pools, combined with inefficient sanitization and repair, implicate pol μ mediated oxidized ribonucleotide insertion as an emerging source of widespread persistent mutagenesis and genomic instability. Nature Publishing Group UK 2021-08-20 /pmc/articles/PMC8379156/ /pubmed/34417448 http://dx.doi.org/10.1038/s41467-021-24486-x Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Jamsen, Joonas A. Sassa, Akira Perera, Lalith Shock, David D. Beard, William A. Wilson, Samuel H. Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair |
title | Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair |
title_full | Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair |
title_fullStr | Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair |
title_full_unstemmed | Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair |
title_short | Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair |
title_sort | structural basis for proficient oxidized ribonucleotide insertion in double strand break repair |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379156/ https://www.ncbi.nlm.nih.gov/pubmed/34417448 http://dx.doi.org/10.1038/s41467-021-24486-x |
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