PIN1 isomerisation of BRCA1 promotes replication fork protection
| Autor: | Joanna R. Morris, Anoop Singh Chauhan, Grant S. Stewart, James F.J. Beesley, Ruth M Densham, Mohammed Jamshad, Manuel Daza-Martin, Jennifer L. Coles, Katarzyna Starowicz |
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| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
Conformational change endocrine system diseases RAD51 Replication fork protection Cell biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine chemistry 030220 oncology & carcinogenesis Prolyl isomerase PIN1 Fork (file system) skin and connective tissue diseases Homologous recombination DNA 030304 developmental biology |
| DOI: | 10.1101/478511 |
| Popis: | BRCA1, BRCA2 and a subset of Fanconi’s Anaemia proteins act to promote RAD51-mediated protection of newly synthesised DNA at stalled replication forks from degradation by nucleases. How BRCA1 contributes, how it is regulated and whether replication fork protection relates to, or differs from, the roles BRCA1 has in homologous recombination is not clear. Here we show that the canonical BRCA1-PALB2 interaction is not required for fork protection and instead we demonstrate that the ability of BRCA1 to protect nascent DNA is regulated in an unexpected fashion through conformational change mediated by the phosphorylation-directed prolyl isomerase, PIN1. BRCA1 isomerisation enhances BRCA1-BARD1 interaction with RAD51 and consequently RAD51 presence at stalled replication structures. Our data suggest BRCA1-BARD1 promotes fork protection in part by enhancing the RAD51 synapse. Patient missense variants in the regulated BRCA1-BARD1 regions similarly show poor nascent strand protection but proficient homologous recombination, defining novel domains required for fork protection in BRCA1-BARD1 associated with cancer predisposition. Together these findings reveal a previously unrecognised pathway that governs BRCA1-mediated replication fork protection. |
| Databáze: | OpenAIRE |
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