| First Author | Mauro M | Year | 2012 |
| Journal | Nucleic Acids Res | Volume | 40 |
| Issue | 17 | Pages | 8348-60 |
| PubMed ID | 22735704 | Mgi Jnum | J:199695 |
| Mgi Id | MGI:5504357 | Doi | 10.1093/nar/gks612 |
| Citation | Mauro M, et al. (2012) p21 promotes error-free replication-coupled DNA double-strand break repair. Nucleic Acids Res 40(17):8348-60 |
| abstractText | 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. |
