2. Academic Validation
  3. RAD51 is chromatin enriched and targetable in BRCA1-deficient cells

RAD51 is chromatin enriched and targetable in BRCA1-deficient cells

  • Mol Cell. 2025 Sep 18;85(18):3373-3387.e6. doi: 10.1016/j.molcel.2025.08.017.
Min Peng 1,  Silviana Lee 1,  Hitha Gopalan Nair 1,  Nathan MacGilvary 1,  Ke Cong 1,  Michitsura Kraemer 1,  Rui Li 1,  Jill McConnell 2,  Christina Baer 2,  Bin Deng 3,  Lihua Zhu 1,  Sharon B Cantor 4
Affiliations

Affiliations

  • 1 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
  • 2 Department of Microbiology and Physiological Systems, Sanderson Center for Optical Experimentation, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
  • 3 Department of Biology, VGN Proteomics Facility, University of Vermont, Burlington, VT 05405, USA.
  • 4 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: sharon.cantor@umassmed.edu.
PMID: 40934926 DOI: 10.1016/j.molcel.2025.08.017
Abstract

BRCA1 mutant cancers are homologous recombination (HR) deficient, and their sensitivity to anti-cancer therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) has long been attributed to this defect. Accordingly, the HR marker, RAD51 foci have been widely used as biomarkers of PARPi response. However, single-stranded DNA (ssDNA) gaps also characterize BRCA1 mutant cells and have been implicated in PARPi sensitivity. Here, unexpectedly, we find that RAD51 is essential and enriched in the chromatin of BRCA1-deficient cells, while additional deletion of 53BP1 alleviates this enrichment and dependency. The same pattern evolves along with PARPi resistance following loss of mediator of DNA damage checkpoint 1 (MDC1) or H2AX. Unlike 53BP1 loss, however, loss of MDC1 and H2AX in BRCA1-deficient cells does not restore RAD51 foci, further uncoupling HR from PARPi resistance. Collectively, we propose a model in which ssDNA gaps in BRCA1-deficient cells necessitate post-replicative RAD51 chromatin engagement for cell fitness, diverting RAD51 from Other roles and revealing a targetable vulnerability.

Keywords

53BP1; BRCA1; H2AX; HR; MDC1; PARPi; RAD51; TLS; foci; gaps.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15317
    99.83%, RAD51 Inhibitor