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p21 promotes error-free replication-coupled DNA double-strand break repair

p21 is a well-established regulator of cell cycle progression. The role of p21 in DNA repair, however, remains poorly characterized. Here, we describe a critical role of p21 in a replication-coupled DNA double-strand break (DSB) repair that is mechanistically distinct from its cell cycle checkpoint...

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Autores principales: Mauro, Maurizio, Rego, Meghan A., Boisvert, Rebecca A., Esashi, Fumiko, Cavallo, Francesca, Jasin, Maria, Howlett, Niall G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458556/
https://www.ncbi.nlm.nih.gov/pubmed/22735704
http://dx.doi.org/10.1093/nar/gks612
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author Mauro, Maurizio
Rego, Meghan A.
Boisvert, Rebecca A.
Esashi, Fumiko
Cavallo, Francesca
Jasin, Maria
Howlett, Niall G.
author_facet Mauro, Maurizio
Rego, Meghan A.
Boisvert, Rebecca A.
Esashi, Fumiko
Cavallo, Francesca
Jasin, Maria
Howlett, Niall G.
author_sort Mauro, Maurizio
collection PubMed
description p21 is a well-established regulator of cell cycle progression. The role of p21 in DNA repair, however, remains poorly characterized. Here, we describe a critical role of p21 in a replication-coupled DNA double-strand break (DSB) repair that is mechanistically distinct from its cell cycle checkpoint function. We demonstrate that p21-deficient cells exhibit elevated chromatid-type aberrations, including gaps and breaks, dicentrics and radial formations, following exposure to several DSB-inducing agents. p21(−/−) cells also exhibit an increased DNA damage-inducible DNA-PK(CS) S2056 phosphorylation, indicative of elevated non-homologous DNA end joining. Concomitantly, p21(−/−) cells are defective in replication-coupled homologous recombination (HR), exhibiting decreased sister chromatid exchanges and HR-dependent repair as determined using a crosslinked GFP reporter assay. Importantly, we establish that the DSB hypersensitivity of p21(−/−) cells is associated with increased cyclin-dependent kinase (CDK)-dependent BRCA2 S3291 phosphorylation and MRE11 nuclear foci formation and can be rescued by inhibition of CDK or MRE11 nuclease activity. Collectively, our results uncover a novel mechanism by which p21 regulates the fidelity of replication-coupled DSB repair and the maintenance of chromosome stability distinct from its role in the G1-S phase checkpoint.
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spelling pubmed-34585562012-09-27 p21 promotes error-free replication-coupled DNA double-strand break repair Mauro, Maurizio Rego, Meghan A. Boisvert, Rebecca A. Esashi, Fumiko Cavallo, Francesca Jasin, Maria Howlett, Niall G. Nucleic Acids Res Genome Integrity, Repair and Replication p21 is a well-established regulator of cell cycle progression. The role of p21 in DNA repair, however, remains poorly characterized. Here, we describe a critical role of p21 in a replication-coupled DNA double-strand break (DSB) repair that is mechanistically distinct from its cell cycle checkpoint function. We demonstrate that p21-deficient cells exhibit elevated chromatid-type aberrations, including gaps and breaks, dicentrics and radial formations, following exposure to several DSB-inducing agents. p21(−/−) cells also exhibit an increased DNA damage-inducible DNA-PK(CS) S2056 phosphorylation, indicative of elevated non-homologous DNA end joining. Concomitantly, p21(−/−) cells are defective in replication-coupled homologous recombination (HR), exhibiting decreased sister chromatid exchanges and HR-dependent repair as determined using a crosslinked GFP reporter assay. Importantly, we establish that the DSB hypersensitivity of p21(−/−) cells is associated with increased cyclin-dependent kinase (CDK)-dependent BRCA2 S3291 phosphorylation and MRE11 nuclear foci formation and can be rescued by inhibition of CDK or MRE11 nuclease activity. Collectively, our results uncover a novel mechanism by which p21 regulates the fidelity of replication-coupled DSB repair and the maintenance of chromosome stability distinct from its role in the G1-S phase checkpoint. Oxford University Press 2012-09 2012-06-25 /pmc/articles/PMC3458556/ /pubmed/22735704 http://dx.doi.org/10.1093/nar/gks612 Text en © The Author(s) 2012. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Genome Integrity, Repair and Replication
Mauro, Maurizio
Rego, Meghan A.
Boisvert, Rebecca A.
Esashi, Fumiko
Cavallo, Francesca
Jasin, Maria
Howlett, Niall G.
p21 promotes error-free replication-coupled DNA double-strand break repair
title p21 promotes error-free replication-coupled DNA double-strand break repair
title_full p21 promotes error-free replication-coupled DNA double-strand break repair
title_fullStr p21 promotes error-free replication-coupled DNA double-strand break repair
title_full_unstemmed p21 promotes error-free replication-coupled DNA double-strand break repair
title_short p21 promotes error-free replication-coupled DNA double-strand break repair
title_sort p21 promotes error-free replication-coupled dna double-strand break repair
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458556/
https://www.ncbi.nlm.nih.gov/pubmed/22735704
http://dx.doi.org/10.1093/nar/gks612
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