Isomerization of BRCA1-BARD1 promotes replication fork protection

Research output: Contribution to journalArticle

External organisations

  • Birmingham Centre for Genome Biology, Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
  • The Institute of Cancer Research, Chester Beatty Laboratories, London, UK.
  • Imperial College London
  • Warwick Medical School, the University of Warwick, Coventry, United Kingdom.
  • Birmingham Centre for Genome Biology and Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. r.m.densham@bham.ac.uk.
  • Birmingham Centre for Genome Biology and Institute of Cancer and Genomic Sciences, Medical and Dental School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK j.morris.3@bham.ac.uk.

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.

Details

Original languageEnglish
Pages (from-to)521-527
Number of pages7
JournalNature
Volume571
Issue number7766
Early online date3 Jul 2019
Publication statusPublished - 25 Jul 2019

Keywords

  • BRCA1 Protein/chemistry, Cell Line, Tumor, DNA Replication/genetics, Genomic Instability/genetics, Humans, Isomerism, Mutation, NIMA-Interacting Peptidylprolyl Isomerase/metabolism, Phosphorylation, Phosphoserine/metabolism, Protein Binding, Rad51 Recombinase/metabolism, Tumor Suppressor Proteins/metabolism, Ubiquitin-Protein Ligases/metabolism