1. Isomerization of BRCA1-BARD1 promotes replication fork protection.
- Author
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Daza-Martin M, Starowicz K, Jamshad M, Tye S, Ronson GE, MacKay HL, Chauhan AS, Walker AK, Stone HR, Beesley JFJ, Coles JL, Garvin AJ, Stewart GS, McCorvie TJ, Zhang X, Densham RM, and Morris JR
- Subjects
- BRCA1 Protein genetics, Cell Line, Tumor, Genomic Instability genetics, Humans, Isomerism, Mutation, NIMA-Interacting Peptidylprolyl Isomerase metabolism, Phosphorylation, Phosphoserine metabolism, Protein Binding, Rad51 Recombinase metabolism, BRCA1 Protein chemistry, BRCA1 Protein metabolism, DNA Replication genetics, Tumor Suppressor Proteins metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1-PALB2 interaction, is required for fork protection. BRCA1-BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1-BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection.
- Published
- 2019
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