P21 promotes error-free replication-coupled DNA double-strand break repair Journal Article
| Authors: | Mauro, M.; Rego, M. A.; Boisvert, R. A.; Esashi, F.; Cavallo, F.; Jasin, M.; Howlett, N. G. |
| Article Title: | P21 promotes error-free replication-coupled DNA double-strand break repair |
| Abstract: | 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-PKCS 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. © 2012 The Author(s). |
| Keywords: | controlled study; dna-binding proteins; nonhuman; dna replication; protein function; animal cell; mouse; animals; mice; mre11 protein; homologous recombination; dna repair; enzyme inhibition; protein depletion; etoposide; green fluorescent protein; camptothecin; hct116 cells; enzyme activity; hela cells; phosphorylation; brca2 protein; enzyme phosphorylation; dna breaks, double-stranded; dna repair enzymes; cell cycle checkpoint; chromosomal instability; sister chromatid exchange; nuclease; double stranded dna break; cell nucleus; cyclin-dependent kinase inhibitor p21; mitomycin; protein p21; protein kinase; protein cross linking; protein dna interaction; cross-linking reagents; chromatid aberration; dna end-joining repair; dna end joining repair; g1 phase cell cycle checkpoint; g1 phase cell cycle checkpoints; recombinational dna repair; topoisomerase inhibitors |
| Journal Title: | Nucleic Acids Research |
| Volume: | 40 |
| Issue: | 17 |
| ISSN: | 0305-1048 |
| Publisher: | Oxford University Press |
| Date Published: | 2012-09-01 |
| Start Page: | 8348 |
| End Page: | 8360 |
| Language: | English |
| DOI: | 10.1093/nar/gks612 |
| PROVIDER: | scopus |
| PMCID: | PMC3458556 |
| PUBMED: | 22735704 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2012" - "CODEN: NARHA" - "Source: Scopus" |
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