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RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles

Author

Listed:
  • Michael A. Longo

    (UT MD Anderson Cancer Center)

  • Sunetra Roy

    (UT MD Anderson Cancer Center)

  • Yue Chen

    (UT MD Anderson Cancer Center)

  • Karl-Heinz Tomaszowski

    (UT MD Anderson Cancer Center)

  • Andrew S. Arvai

    (The Scripps Research Institute)

  • Jordan T. Pepper

    (University of Calgary)

  • Rebecca A. Boisvert

    (UT MD Anderson Cancer Center)

  • Selvi Kunnimalaiyaan

    (UT MD Anderson Cancer Center)

  • Caezanne Keshvani

    (UT MD Anderson Cancer Center)

  • David Schild

    (Lawrence Berkeley National Laboratory)

  • Albino Bacolla

    (UT MD Anderson Cancer Center)

  • Gareth J. Williams

    (University of Calgary)

  • John A. Tainer

    (UT MD Anderson Cancer Center
    UT MD Anderson Cancer Center)

  • Katharina Schlacher

    (UT MD Anderson Cancer Center)

Abstract

RAD51C is an enigmatic predisposition gene for breast, ovarian, and prostate cancer. Currently, missing structural and related functional understanding limits patient mutation interpretation to homology-directed repair (HDR) function analysis. Here we report the RAD51C-XRCC3 (CX3) X-ray co-crystal structure with bound ATP analog and define separable RAD51C replication stability roles informed by its three-dimensional structure, assembly, and unappreciated polymerization motif. Mapping of cancer patient mutations as a functional guide confirms ATP-binding matching RAD51 recombinase, yet highlights distinct CX3 interfaces. Analyses of CRISPR/Cas9-edited human cells with RAD51C mutations combined with single-molecule, single-cell and biophysics measurements uncover discrete CX3 regions for DNA replication fork protection, restart and reversal, accomplished by separable functions in DNA binding and implied 5’ RAD51 filament capping. Collective findings establish CX3 as a cancer-relevant replication stress response complex, show how HDR-proficient variants could contribute to tumor development, and identify regions to aid functional testing and classification of cancer mutations.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40096-1
    DOI: 10.1038/s41467-023-40096-1
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    References listed on IDEAS

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    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Joost van Mameren & Mauro Modesti & Roland Kanaar & Claire Wyman & Erwin J. G. Peterman & Gijs J. L. Wuite, 2009. "Counting RAD51 proteins disassembling from nucleoprotein filaments under tension," Nature, Nature, vol. 457(7230), pages 745-748, February.
    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    4. 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.
    5. Karl-Heinz Tomaszowski & Sunetra Roy & Carolina Guerrero & Poojan Shukla & Caezaan Keshvani & Yue Chen & Martina Ott & Xiaogang Wu & Jianhua Zhang & Courtney D. DiNardo & Detlev Schindler & Katharina , 2023. "Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
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    Cited by:

    1. Zu Ye & Shengfeng Xu & Yin Shi & Xueqian Cheng & Yuan Zhang & Sunetra Roy & Sarita Namjoshi & Michael A. Longo & Todd M. Link & Katharina Schlacher & Guang Peng & Dihua Yu & Bin Wang & John A. Tainer , 2024. "GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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