Isomerization of BRCA1–BARD1 promotes replication fork protection

Manuel Daza-Martin, Katarzyna Starowicz, Mohammed Jamshad, Stephanie Tye, George E. Ronson, Hannah L. MacKay, Anoop Singh Chauhan, Alexandra K. Walker, Helen R. Stone, James F. J. Beesley, Jennifer L. Coles, Alexander J. Garvin, Grant S. Stewart, Thomas J. McCorvie, Xiaodong Zhang, Ruth M. Densham () and Joanna R. Morris ()
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Manuel Daza-Martin: University of Birmingham
Katarzyna Starowicz: University of Birmingham
Mohammed Jamshad: University of Birmingham
Stephanie Tye: Imperial College London
George E. Ronson: University of Birmingham
Hannah L. MacKay: University of Birmingham
Anoop Singh Chauhan: University of Birmingham
Alexandra K. Walker: University of Birmingham
Helen R. Stone: University of Birmingham
James F. J. Beesley: University of Birmingham
Jennifer L. Coles: University of Birmingham
Alexander J. Garvin: University of Birmingham
Grant S. Stewart: University of Birmingham
Thomas J. McCorvie: Imperial College London
Xiaodong Zhang: Imperial College London
Ruth M. Densham: University of Birmingham
Joanna R. Morris: University of Birmingham

Nature, 2019, vol. 571, issue 7766, 521-527

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1363-4

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