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EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2
Accurate DNA replication is essential to preserve genomic integrity and prevent chromosomal instability-associated diseases including cancer. Key to this process is the cells’ ability to stabilize and restart stalled replication forks. Here, we show that the EXD2 nuclease is essential to this proces...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695479/ https://www.ncbi.nlm.nih.gov/pubmed/31255466 http://dx.doi.org/10.1016/j.molcel.2019.05.026 |
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author | Nieminuszczy, Jadwiga Broderick, Ronan Bellani, Marina A. Smethurst, Elizabeth Schwab, Rebekka A. Cherdyntseva, Veronica Evmorfopoulou, Theodora Lin, Yea-Lih Minczuk, Michal Pasero, Philippe Gagos, Sarantis Seidman, Michael M. Niedzwiedz, Wojciech |
author_facet | Nieminuszczy, Jadwiga Broderick, Ronan Bellani, Marina A. Smethurst, Elizabeth Schwab, Rebekka A. Cherdyntseva, Veronica Evmorfopoulou, Theodora Lin, Yea-Lih Minczuk, Michal Pasero, Philippe Gagos, Sarantis Seidman, Michael M. Niedzwiedz, Wojciech |
author_sort | Nieminuszczy, Jadwiga |
collection | PubMed |
description | Accurate DNA replication is essential to preserve genomic integrity and prevent chromosomal instability-associated diseases including cancer. Key to this process is the cells’ ability to stabilize and restart stalled replication forks. Here, we show that the EXD2 nuclease is essential to this process. EXD2 recruitment to stressed forks suppresses their degradation by restraining excessive fork regression. Accordingly, EXD2 deficiency leads to fork collapse, hypersensitivity to replication inhibitors, and genomic instability. Impeding fork regression by inactivation of SMARCAL1 or removal of RECQ1’s inhibition in EXD2(−/−) cells restores efficient fork restart and genome stability. Moreover, purified EXD2 efficiently processes substrates mimicking regressed forks. Thus, this work identifies a mechanism underpinned by EXD2’s nuclease activity, by which cells balance fork regression with fork restoration to maintain genome stability. Interestingly, from a clinical perspective, we discover that EXD2’s depletion is synthetic lethal with mutations in BRCA1/2, implying a non-redundant role in replication fork protection. |
format | Online Article Text |
id | pubmed-6695479 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-66954792019-08-19 EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2 Nieminuszczy, Jadwiga Broderick, Ronan Bellani, Marina A. Smethurst, Elizabeth Schwab, Rebekka A. Cherdyntseva, Veronica Evmorfopoulou, Theodora Lin, Yea-Lih Minczuk, Michal Pasero, Philippe Gagos, Sarantis Seidman, Michael M. Niedzwiedz, Wojciech Mol Cell Article Accurate DNA replication is essential to preserve genomic integrity and prevent chromosomal instability-associated diseases including cancer. Key to this process is the cells’ ability to stabilize and restart stalled replication forks. Here, we show that the EXD2 nuclease is essential to this process. EXD2 recruitment to stressed forks suppresses their degradation by restraining excessive fork regression. Accordingly, EXD2 deficiency leads to fork collapse, hypersensitivity to replication inhibitors, and genomic instability. Impeding fork regression by inactivation of SMARCAL1 or removal of RECQ1’s inhibition in EXD2(−/−) cells restores efficient fork restart and genome stability. Moreover, purified EXD2 efficiently processes substrates mimicking regressed forks. Thus, this work identifies a mechanism underpinned by EXD2’s nuclease activity, by which cells balance fork regression with fork restoration to maintain genome stability. Interestingly, from a clinical perspective, we discover that EXD2’s depletion is synthetic lethal with mutations in BRCA1/2, implying a non-redundant role in replication fork protection. Cell Press 2019-08-08 /pmc/articles/PMC6695479/ /pubmed/31255466 http://dx.doi.org/10.1016/j.molcel.2019.05.026 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Nieminuszczy, Jadwiga Broderick, Ronan Bellani, Marina A. Smethurst, Elizabeth Schwab, Rebekka A. Cherdyntseva, Veronica Evmorfopoulou, Theodora Lin, Yea-Lih Minczuk, Michal Pasero, Philippe Gagos, Sarantis Seidman, Michael M. Niedzwiedz, Wojciech EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2 |
title | EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2 |
title_full | EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2 |
title_fullStr | EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2 |
title_full_unstemmed | EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2 |
title_short | EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2 |
title_sort | exd2 protects stressed replication forks and is required for cell viability in the absence of brca1/2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695479/ https://www.ncbi.nlm.nih.gov/pubmed/31255466 http://dx.doi.org/10.1016/j.molcel.2019.05.026 |
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