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Isomerization of BRCA1–BARD1 promotes replication fork protection

Author

Listed:
  • Manuel Daza-Martin

    (University of Birmingham
    Chester Beatty Laboratories)

  • 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
    The University of Warwick)

  • 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)

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.

Suggested Citation

  • 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 & J, 2019. "Isomerization of BRCA1–BARD1 promotes replication fork protection," Nature, Nature, vol. 571(7766), pages 521-527, July.
    • Handle: RePEc:nat:nature:v:571:y:2019:i:7766:d:10.1038_s41586-019-1363-4
    DOI: 10.1038/s41586-019-1363-4
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    Cited by:

    1. Qiuhong Zhu & Panpan Liang & Hao Meng & Fangzhen Li & Wei Miao & Cuiying Chu & Wei Wang & Dongxue Li & Cong Chen & Yu Shi & Xingjiang Yu & Yifang Ping & Chaoshi Niu & Hai-bo Wu & Aili Zhang & Xiu-wu B, 2024. "Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Daniel Salas-Lloret & Néstor García-Rodríguez & Emily Soto-Hidalgo & Lourdes González-Vinceiro & Carmen Espejo-Serrano & Lisanne Giebel & María Luisa Mateos-Martín & Arnoud H. Ru & Peter A. Veelen & P, 2024. "BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Youngho Kwon & Heike Rösner & Weixing Zhao & Platon Selemenakis & Zhuoling He & Ajinkya S. Kawale & Jeffrey N. Katz & Cody M. Rogers & Francisco E. Neal & Aida Badamchi Shabestari & Valdemaras Petrosi, 2023. "DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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