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PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells
Acute treatment with replication-stalling chemotherapeutics causes reversal of replication forks. BRCA proteins protect reversed forks from nucleolytic degradation, and their loss leads to chemosensitivity. Here, we show that fork degradation is no longer detectable in BRCA1-deficient cancer cells e...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007862/ https://www.ncbi.nlm.nih.gov/pubmed/31676232 http://dx.doi.org/10.1016/j.molcel.2019.10.008 |
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author | Quinet, Annabel Tirman, Stephanie Jackson, Jessica Šviković, Saša Lemaçon, Delphine Carvajal-Maldonado, Denisse González-Acosta, Daniel Vessoni, Alexandre T. Cybulla, Emily Wood, Matthew Tavis, Steven Batista, Luis F.Z. Méndez, Juan Sale, Julian E. Vindigni, Alessandro |
author_facet | Quinet, Annabel Tirman, Stephanie Jackson, Jessica Šviković, Saša Lemaçon, Delphine Carvajal-Maldonado, Denisse González-Acosta, Daniel Vessoni, Alexandre T. Cybulla, Emily Wood, Matthew Tavis, Steven Batista, Luis F.Z. Méndez, Juan Sale, Julian E. Vindigni, Alessandro |
author_sort | Quinet, Annabel |
collection | PubMed |
description | Acute treatment with replication-stalling chemotherapeutics causes reversal of replication forks. BRCA proteins protect reversed forks from nucleolytic degradation, and their loss leads to chemosensitivity. Here, we show that fork degradation is no longer detectable in BRCA1-deficient cancer cells exposed to multiple cisplatin doses, mimicking a clinical treatment regimen. This effect depends on increased expression and chromatin loading of PRIMPOL and is regulated by ATR activity. Electron microscopy and single-molecule DNA fiber analyses reveal that PRIMPOL rescues fork degradation by reinitiating DNA synthesis past DNA lesions. PRIMPOL repriming leads to accumulation of ssDNA gaps while suppressing fork reversal. We propose that cells adapt to repeated cisplatin doses by activating PRIMPOL repriming under conditions that would otherwise promote pathological reversed fork degradation. This effect is generalizable to other conditions of impaired fork reversal (e.g., SMARCAL1 loss or PARP inhibition) and suggests a new strategy to modulate cisplatin chemosensitivity by targeting the PRIMPOL pathway. |
format | Online Article Text |
id | pubmed-7007862 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-70078622020-10-22 PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells Quinet, Annabel Tirman, Stephanie Jackson, Jessica Šviković, Saša Lemaçon, Delphine Carvajal-Maldonado, Denisse González-Acosta, Daniel Vessoni, Alexandre T. Cybulla, Emily Wood, Matthew Tavis, Steven Batista, Luis F.Z. Méndez, Juan Sale, Julian E. Vindigni, Alessandro Mol Cell Article Acute treatment with replication-stalling chemotherapeutics causes reversal of replication forks. BRCA proteins protect reversed forks from nucleolytic degradation, and their loss leads to chemosensitivity. Here, we show that fork degradation is no longer detectable in BRCA1-deficient cancer cells exposed to multiple cisplatin doses, mimicking a clinical treatment regimen. This effect depends on increased expression and chromatin loading of PRIMPOL and is regulated by ATR activity. Electron microscopy and single-molecule DNA fiber analyses reveal that PRIMPOL rescues fork degradation by reinitiating DNA synthesis past DNA lesions. PRIMPOL repriming leads to accumulation of ssDNA gaps while suppressing fork reversal. We propose that cells adapt to repeated cisplatin doses by activating PRIMPOL repriming under conditions that would otherwise promote pathological reversed fork degradation. This effect is generalizable to other conditions of impaired fork reversal (e.g., SMARCAL1 loss or PARP inhibition) and suggests a new strategy to modulate cisplatin chemosensitivity by targeting the PRIMPOL pathway. Cell Press 2020-02-06 /pmc/articles/PMC7007862/ /pubmed/31676232 http://dx.doi.org/10.1016/j.molcel.2019.10.008 Text en © 2020 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. 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 Quinet, Annabel Tirman, Stephanie Jackson, Jessica Šviković, Saša Lemaçon, Delphine Carvajal-Maldonado, Denisse González-Acosta, Daniel Vessoni, Alexandre T. Cybulla, Emily Wood, Matthew Tavis, Steven Batista, Luis F.Z. Méndez, Juan Sale, Julian E. Vindigni, Alessandro PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells |
title | PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells |
title_full | PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells |
title_fullStr | PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells |
title_full_unstemmed | PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells |
title_short | PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells |
title_sort | primpol-mediated adaptive response suppresses replication fork reversal in brca-deficient cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007862/ https://www.ncbi.nlm.nih.gov/pubmed/31676232 http://dx.doi.org/10.1016/j.molcel.2019.10.008 |
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