Cargando…
The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks
Mismatch repair (MMR) is a replication-coupled DNA repair mechanism and plays multiple roles at the replication fork. The well-established MMR functions include correcting misincorporated nucleotides that have escaped the proofreading activity of DNA polymerases, recognizing nonmismatched DNA adduct...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546528/ https://www.ncbi.nlm.nih.gov/pubmed/36161943 http://dx.doi.org/10.1073/pnas.2201738119 |
_version_ | 1784805060097605632 |
---|---|
author | Zhang, Junqiu Zhao, Xin Liu, Lu Li, Hao-Dong Gu, Liya Castrillon, Diego H. Li, Guo-Min |
author_facet | Zhang, Junqiu Zhao, Xin Liu, Lu Li, Hao-Dong Gu, Liya Castrillon, Diego H. Li, Guo-Min |
author_sort | Zhang, Junqiu |
collection | PubMed |
description | Mismatch repair (MMR) is a replication-coupled DNA repair mechanism and plays multiple roles at the replication fork. The well-established MMR functions include correcting misincorporated nucleotides that have escaped the proofreading activity of DNA polymerases, recognizing nonmismatched DNA adducts, and triggering a DNA damage response. In an attempt to determine whether MMR regulates replication progression in cells expressing an ultramutable DNA polymerase ɛ (Polɛ), carrying a proline-to-arginine substitution at amino acid 286 (Polɛ-P286R), we identified an unusual MMR function in response to hydroxyurea (HU)-induced replication stress. Polɛ-P286R cells treated with hydroxyurea exhibit increased MRE11-catalyzed nascent strand degradation. This degradation by MRE11 depends on the mismatch recognition protein MutSα and its binding to stalled replication forks. Increased MutSα binding at replication forks is also associated with decreased loading of replication fork protection factors FANCD2 and BRCA1, suggesting blockage of these fork protection factors from loading to replication forks by MutSα. We find that the MutSα-dependent MRE11-catalyzed fork degradation induces DNA breaks and various chromosome abnormalities. Therefore, unlike the well-known MMR functions of ensuring replication fidelity, the newly identified MMR activity of promoting genome instability may also play a role in cancer avoidance by eliminating rogue cells. |
format | Online Article Text |
id | pubmed-9546528 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-95465282022-10-08 The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks Zhang, Junqiu Zhao, Xin Liu, Lu Li, Hao-Dong Gu, Liya Castrillon, Diego H. Li, Guo-Min Proc Natl Acad Sci U S A Biological Sciences Mismatch repair (MMR) is a replication-coupled DNA repair mechanism and plays multiple roles at the replication fork. The well-established MMR functions include correcting misincorporated nucleotides that have escaped the proofreading activity of DNA polymerases, recognizing nonmismatched DNA adducts, and triggering a DNA damage response. In an attempt to determine whether MMR regulates replication progression in cells expressing an ultramutable DNA polymerase ɛ (Polɛ), carrying a proline-to-arginine substitution at amino acid 286 (Polɛ-P286R), we identified an unusual MMR function in response to hydroxyurea (HU)-induced replication stress. Polɛ-P286R cells treated with hydroxyurea exhibit increased MRE11-catalyzed nascent strand degradation. This degradation by MRE11 depends on the mismatch recognition protein MutSα and its binding to stalled replication forks. Increased MutSα binding at replication forks is also associated with decreased loading of replication fork protection factors FANCD2 and BRCA1, suggesting blockage of these fork protection factors from loading to replication forks by MutSα. We find that the MutSα-dependent MRE11-catalyzed fork degradation induces DNA breaks and various chromosome abnormalities. Therefore, unlike the well-known MMR functions of ensuring replication fidelity, the newly identified MMR activity of promoting genome instability may also play a role in cancer avoidance by eliminating rogue cells. National Academy of Sciences 2022-09-26 2022-10-04 /pmc/articles/PMC9546528/ /pubmed/36161943 http://dx.doi.org/10.1073/pnas.2201738119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Zhang, Junqiu Zhao, Xin Liu, Lu Li, Hao-Dong Gu, Liya Castrillon, Diego H. Li, Guo-Min The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks |
title | The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks |
title_full | The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks |
title_fullStr | The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks |
title_full_unstemmed | The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks |
title_short | The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks |
title_sort | mismatch recognition protein mutsα promotes nascent strand degradation at stalled replication forks |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546528/ https://www.ncbi.nlm.nih.gov/pubmed/36161943 http://dx.doi.org/10.1073/pnas.2201738119 |
work_keys_str_mv | AT zhangjunqiu themismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT zhaoxin themismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT liulu themismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT lihaodong themismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT guliya themismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT castrillondiegoh themismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT liguomin themismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT zhangjunqiu mismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT zhaoxin mismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT liulu mismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT lihaodong mismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT guliya mismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT castrillondiegoh mismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks AT liguomin mismatchrecognitionproteinmutsapromotesnascentstranddegradationatstalledreplicationforks |