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

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 R. Radke, Patricia L. Opresko, Judith L. Yanowitz, Eric C. Greene, Jung-Min Lee, Susan M. Domchek, Elizabeth M. Swisher, Shaun K. Olsen, Patrick Sung and Kara A. Bernstein ()
Additional contact information
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
Marc R. Radke: University of Washington School of Medicine
Patricia L. Opresko: University of Pittsburgh School of Public Health
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

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61283-2

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