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Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide
Oxidized dGTP (8-oxo-7,8-dihydro-2´-deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly unde...
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/PMC8024293/ https://www.ncbi.nlm.nih.gov/pubmed/33824325 http://dx.doi.org/10.1038/s41467-021-21354-6 |
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author | Jamsen, Joonas A. Sassa, Akira Shock, David D. Beard, William A. Wilson, Samuel H. |
author_facet | Jamsen, Joonas A. Sassa, Akira Shock, David D. Beard, William A. Wilson, Samuel H. |
author_sort | Jamsen, Joonas A. |
collection | PubMed |
description | Oxidized dGTP (8-oxo-7,8-dihydro-2´-deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly understood. High-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase μ undergoing DNA synthesis reveal that a third active site metal promotes insertion of oxidized and undamaged dGTP in the canonical anti-conformation opposite template cytosine. The product metal bridged O8 with product oxygens, and was not observed in the syn-conformation opposite template adenine (A(t)). Rotation of A(t) into the syn-conformation enabled undamaged dGTP misinsertion. Exploiting metal and substrate dynamics in a rigid active site allows 8-oxodGTP to circumvent polymerase fidelity safeguards to promote pro-mutagenic double strand break repair. |
format | Online Article Text |
id | pubmed-8024293 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-80242932021-04-21 Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide Jamsen, Joonas A. Sassa, Akira Shock, David D. Beard, William A. Wilson, Samuel H. Nat Commun Article Oxidized dGTP (8-oxo-7,8-dihydro-2´-deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly understood. High-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase μ undergoing DNA synthesis reveal that a third active site metal promotes insertion of oxidized and undamaged dGTP in the canonical anti-conformation opposite template cytosine. The product metal bridged O8 with product oxygens, and was not observed in the syn-conformation opposite template adenine (A(t)). Rotation of A(t) into the syn-conformation enabled undamaged dGTP misinsertion. Exploiting metal and substrate dynamics in a rigid active site allows 8-oxodGTP to circumvent polymerase fidelity safeguards to promote pro-mutagenic double strand break repair. Nature Publishing Group UK 2021-04-06 /pmc/articles/PMC8024293/ /pubmed/33824325 http://dx.doi.org/10.1038/s41467-021-21354-6 Text en © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 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/. |
spellingShingle | Article Jamsen, Joonas A. Sassa, Akira Shock, David D. Beard, William A. Wilson, Samuel H. Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide |
title | Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide |
title_full | Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide |
title_fullStr | Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide |
title_full_unstemmed | Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide |
title_short | Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide |
title_sort | watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024293/ https://www.ncbi.nlm.nih.gov/pubmed/33824325 http://dx.doi.org/10.1038/s41467-021-21354-6 |
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