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Sequential role of RAD51 paralog complexes in replication fork remodeling and restart

Author

Listed:
  • Matteo Berti

    (University of Zurich)

  • Federico Teloni

    (University of Zurich)

  • Sofija Mijic

    (University of Zurich)

  • Sebastian Ursich

    (University of Zurich)

  • Jevgenij Fuchs

    (University of Zurich)

  • Maria Dilia Palumbieri

    (University of Zurich)

  • Jana Krietsch

    (University of Zurich)

  • Jonas A. Schmid

    (University of Zurich)

  • Edwige B. Garcin

    (Cancer Research Center of Marseille; CNRS; Inserm; Institut Paoli-Calmettes; Aix-Marseille Université)

  • Stéphanie Gon

    (Cancer Research Center of Marseille; CNRS; Inserm; Institut Paoli-Calmettes; Aix-Marseille Université)

  • Mauro Modesti

    (Cancer Research Center of Marseille; CNRS; Inserm; Institut Paoli-Calmettes; Aix-Marseille Université)

  • Matthias Altmeyer

    (University of Zurich)

  • Massimo Lopes

    (University of Zurich)

Abstract

Homologous recombination (HR) factors were recently implicated in DNA replication fork remodeling and protection. While maintaining genome stability, HR-mediated fork remodeling promotes cancer chemoresistance, by as-yet elusive mechanisms. Five HR cofactors – the RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 – recently emerged as crucial tumor suppressors. Albeit extensively characterized in DNA repair, their role in replication has not been addressed systematically. Here, we identify all RAD51 paralogs while screening for modulators of RAD51 recombinase upon replication stress. Single-molecule analysis of fork progression and architecture in isogenic cellular systems shows that the BCDX2 subcomplex restrains fork progression upon stress, promoting fork reversal. Accordingly, BCDX2 primes unscheduled degradation of reversed forks in BRCA2-defective cells, boosting genomic instability. Conversely, the CX3 subcomplex is dispensable for fork reversal, but mediates efficient restart of reversed forks. We propose that RAD51 paralogs sequentially orchestrate clinically relevant transactions at replication forks, cooperatively promoting fork remodeling and restart.

Suggested Citation

  • Matteo Berti & Federico Teloni & Sofija Mijic & Sebastian Ursich & Jevgenij Fuchs & Maria Dilia Palumbieri & Jana Krietsch & Jonas A. Schmid & Edwige B. Garcin & Stéphanie Gon & Mauro Modesti & Matthi, 2020. "Sequential role of RAD51 paralog complexes in replication fork remodeling and restart," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17324-z
    DOI: 10.1038/s41467-020-17324-z
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    References listed on IDEAS

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    1. Roger D. Johnson & Nan Liu & Maria Jasin, 1999. "Mammalian XRCC2 promotes the repair of DNA double-strand breaks by homologous recombination," Nature, Nature, vol. 401(6751), pages 397-399, September.
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    Cited by:

    1. Junliang Chen & Mingjie Wu & Yulan Yang & Chunyan Ruan & Yi Luo & Lizhi Song & Ting Wu & Jun Huang & Bing Yang & Ting Liu, 2024. "TFIP11 promotes replication fork reversal to preserve genome stability," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Michael A. Longo & Sunetra Roy & Yue Chen & Karl-Heinz Tomaszowski & Andrew S. Arvai & Jordan T. Pepper & Rebecca A. Boisvert & Selvi Kunnimalaiyaan & Caezanne Keshvani & David Schild & Albino Bacolla, 2023. "RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Maria Dilia Palumbieri & Chiara Merigliano & Daniel González-Acosta & Danina Kuster & Jana Krietsch & Henriette Stoy & Thomas Känel & Svenja Ulferts & Bettina Welter & Joël Frey & Cyril Doerdelmann & , 2023. "Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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