p21 promotes error-free replication-coupled DNA double-strand break repair
| Autor: | Rebecca A. Boisvert, Francesca Cavallo, Meghan A. Rego, Niall G. Howlett, Fumiko Esashi, Maurizio Mauro, Maria Jasin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
DNA Replication DNA End-Joining Repair Cell cycle checkpoint DNA Repair Topoisomerase Inhibitors DNA repair Mitomycin Genome Integrity Repair and Replication Biology Mice 03 medical and health sciences 0302 clinical medicine Cyclin-dependent kinase Chromosomal Instability Genetics Animals Humans DNA Breaks Double-Stranded Phosphorylation Etoposide 030304 developmental biology BRCA2 Protein MRE11 Homologue Protein 0303 health sciences Recombinational DNA Repair Cell cycle G2-M DNA damage checkpoint DNA repair protein XRCC4 HCT116 Cells G1 Phase Cell Cycle Checkpoints Molecular biology Double Strand Break Repair 3. Good health DNA-Binding Proteins enzymes and coenzymes (carbohydrates) Cross-Linking Reagents DNA Repair Enzymes 030220 oncology & carcinogenesis biology.protein Camptothecin biological phenomena cell phenomena and immunity Homologous recombination HeLa Cells |
| Zdroj: | Nucleic Acids Research |
| Popis: | 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 DSBinducing agents. p21 � /� cells also exhibit an increased DNA damage-inducible DNA-PKCS S2056 phosphorylation, indicative of elevated nonhomologous DNA end joining. Concomitantly, p21 � /� cells are defective in replication-coupled homologous recombination (HR), exhibiting decreased sister chromatid exchanges and HRdependent 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. |
| Databáze: | OpenAIRE |
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