RAD51C breast cancer-identified variants with attenuated homologous recombination function exhibit sensitivity to combined PARP1 and ATR inhibition - Abstract

Sep 23, 2026

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The tumor suppressor RAD51C is essential for DNA double-strand break repair via the homologous recombination (HR) pathway. RAD51C loss increases breast cancer risk, yet most patient RAD51C missense mutations remain variants of unknown significance. This study characterizes 33 clinically identified breast cancer RAD51C variants, identifying one HR-deficient and five with intermediate HR activity. Attenuated HR variants misregulate replication fork progression, accumulate single-strand DNA gaps, and show enhanced sensitivity to combined PARP1 and ATR inhibition in a responsive subset.

LanguageEnglish

CategoryHealthcare

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Reading Time33 min

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Abstract

Introduction

RAD51C and homologous recombination in cancer risk

RAD51 paralogs and replication-associated functions

NAR Cancer, 2026, 8, zcag018 [https://doi.org/10.1093/narcan/zcag018](https://doi.org/10.1093/narcan/zcag018) DNA Damage Sensing and Repair RAD51C breast cancer-identified variants with attenuated homologous recombination function exhibit sensitivity to combined PARP1 and ATR inhibition Gayatri S. Ganesan1 ,†, Zoë R. Moosbrugger1 ,†, Phoebe S. Parker1,2 , Noah J. Goff 1 , Arjun K. Kumar1 , Kara A. Bernstein 1 ,* 1 Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States 2 Current address: Department of Cancer Biology, Washington University in Saint Louis, Saint Louis, MO 63110, United States ∗ To whom correspondence should be addressed. Email: [kara.bernstein@pennmedicine.upenn.edu](kara.bernstein@pennmedicine.upenn.edu)[ ](kara.bernstein@pennmedicine.upenn.edu)†The first two authors should be regarded as Joint First Authors. Abstract The tumor suppressor RAD51C is essential for DNA double-strand break repair through the homologous recombination (HR) pathway. RAD51C loss is linked to an increased risk of breast cancer, but the majority of RAD51C missense mutations identified in patients are variants of unknown significance. In addition to promoting HR, RAD51C also protects damaged replication forks. Here, we characterized 33 clinically identified breast cancer variants and assayed their ability to perform HR. We identified one HR-deficient variant and five variants with intermediate HR proficiency. While these variants have modestly attenuated HR, they misregulate replication fork progression and accumulate single-strand DNA gaps. We then assessed their sensitivity to PARP1 and ATR inhibition. While RAD51C variants with attenuated HR are largely resistant to monotherapy, cells expressing a subset of these RAD51C variants exhibit increased sensitivity to combination PARP1i and ATRi treatment, Saruparib and Ceralasertib, respectively. Collectively, we pinpoint the key functional regions of RAD51C and uncover a new C-terminal region proximal to the ATP-binding site in the folded RAD51C structure. Together, our findings suggest that variants with partial HR function can cause profound defects in the repair of replicative damage, and that this, in turn, may lead to distinct therapeutic responses. Graphical abstract Received: May 1, 2026. Revised: June 11, 2026. Accepted: July 9, 2026 © The Author(s) 2026 . Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ([https://creativecommons.org/licenses/by-nc/4.0/](https://creativecommons.org/licenses/by-nc/4.0/)), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [reprints@oup.com](reprints@oup.com) for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [journals.permissions@oup.com](journals.permissions@oup.com). 2 Ganesan et al. Introduction Homologous recombination (HR) is a high-fidelity DNA repair pathway used to repair double-strand breaks (DSBs) . Germline defects in HR genes such as BRCA1, BRCA2, PALB2, BARD1, RAD51C, and RAD51D have been linked to increased risk for breast and/or ovarian cancers [3–6] . Given the close association with cancer risk, HR genes are included on hereditary breast and ovarian cancer genetic screening panels. While nonsense variants are readily classified as pathogenic, the majority of variants observed in tumors are missense variants. Though missense variants in genes such as BRCA1 and BRCA2 have been well characterized [7–9], many other HR genes linked to cancer are less well understood, including RAD51C. Many missense variants of RAD51C have been identified in patients

FAQs

How was RAD51C variant function assessed in this study?

Thirty-three clinically identified RAD51C breast cancer variants were characterized and assayed for their ability to perform homologous recombination (HR).

What functional defects were observed in variants with attenuated HR?

These variants misregulate replication fork progression and accumulate single-strand DNA gaps.

Do attenuated-HR RAD51C variants respond to PARP1 and ATR inhibition?

They are largely resistant to PARP1 or ATR monotherapy, but a subset shows increased sensitivity to combined PARP1 inhibition and ATR inhibition using Saruparib and Ceralasertib, respectively.

Sep 23, 2026

Uploaded by OmBimo