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Comprehensive RAD51C ovarian cancer variant analysis uncouples homologous recombination and replicative functions

Author

Listed:
  • Hayley L. Rein

    (Department of Pharmacology and Chemical Biology)

  • Yashpal Rawal

    (Greehey Children’s Cancer Research Institute)

  • Anna L. Palovcak-Lightbourn

    (Department of Biochemistry and Biophysics)

  • Gayatri S. Ganesan

    (Department of Biochemistry and Biophysics)

  • Phoebe S. Parker

    (Department of Biochemistry and Biophysics)

  • Reagan Russell

    (Department of Pharmacology and Chemical Biology)

  • Kristie E. Darrah

    (Department of Biochemistry and Biophysics)

  • Mohammad Afsar

    (Greehey Children’s Cancer Research Institute)

  • Meghan R. Sullivan

    (Department of Microbiology and Molecular Genetics)

  • Sarah R. Hengel

    (Department of Pharmacology and Chemical Biology
    Tufts University)

  • Marc R. Radke

    (University of Washington School of Medicine)

  • Patricia L. Opresko

    (University of Pittsburgh School of Public Health
    UPMC Hillman Cancer Center)

  • Judith L. Yanowitz

    (and Reproductive Science)

  • Eric C. Greene

    (Columbia University Medical Center)

  • Jung-Min Lee

    (National Cancer Institute)

  • Susan M. Domchek

    (University of Pennsylvania School of Medicine)

  • Elizabeth M. Swisher

    (University of Washington School of Medicine)

  • Shaun K. Olsen

    (Greehey Children’s Cancer Research Institute)

  • Patrick Sung

    (Greehey Children’s Cancer Research Institute)

  • Kara A. Bernstein

    (Department of Biochemistry and Biophysics)

Abstract

RAD51C is a tumor suppressor gene with over 285 variants of unknown significance (VUS) found in primary ovarian tumors. RAD51C is a paralog of the recombinase RAD51, and it forms complexes with other paralogs to regulate RAD51 activity. We screened 27 ovarian cancer-derived RAD51C VUS to identify those that affect the assembly of functional tetrameric RAD51B-C-D-XRCC2 (BCDX2) complex. With yeast 3-hybrid and biochemical analyses, we identify a mutation cluster of the RAD51C Walker B region affecting protein interactions with other RAD51 paralogs. By further analyzing these variants for homologous recombination (HR), replication fork regression, DNA binding and ATPase activity, and RAD51 filament formation, we identified separation-of-function alleles that uncouple RAD51C distinct enzymatic activities with HR and replication. Thus, our analysis of RAD51C identifies additional VUS with functional defects, which will aid in pathogenicity classification and inform future strategies to treat individuals harboring RAD51C loss-of-function alleles.

Suggested Citation

  • Hayley L. Rein & Yashpal Rawal & Anna L. Palovcak-Lightbourn & Gayatri S. Ganesan & Phoebe S. Parker & Reagan Russell & Kristie E. Darrah & Mohammad Afsar & Meghan R. Sullivan & Sarah R. Hengel & Marc, 2025. "Comprehensive RAD51C ovarian cancer variant analysis uncouples homologous recombination and replicative functions," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61283-2
    DOI: 10.1038/s41467-025-61283-2
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    References listed on IDEAS

    as
    1. Edwige B Garcin & Stéphanie Gon & Meghan R Sullivan & Gregory J Brunette & Anne De Cian & Jean-Paul Concordet & Carine Giovannangeli & Wilhelm G Dirks & Sonja Eberth & Kara A Bernstein & Rohit Prakash, 2019. "Differential Requirements for the RAD51 Paralogs in Genome Repair and Maintenance in Human Cells," PLOS Genetics, Public Library of Science, vol. 15(10), pages 1-29, October.
    2. 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.
    3. Yashpal Rawal & Lijia Jia & Aviv Meir & Shuo Zhou & Hardeep Kaur & Eliza A. Ruben & Youngho Kwon & Kara A. Bernstein & Maria Jasin & Alexander B. Taylor & Sandeep Burma & Robert Hromas & Alexander V. , 2023. "Structural insights into BCDX2 complex function in homologous recombination," Nature, Nature, vol. 619(7970), pages 640-649, July.
    4. 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.
    5. Luke A. Greenhough & Chih-Chao Liang & Ondrej Belan & Simone Kunzelmann & Sarah Maslen & Monica C. Rodrigo-Brenni & Roopesh Anand & Mark Skehel & Simon J. Boulton & Stephen C. West, 2023. "Structure and function of the RAD51B–RAD51C–RAD51D–XRCC2 tumour suppressor," Nature, Nature, vol. 619(7970), pages 650-657, July.
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