BRCA2 deficiency and replication stress drive APOBEC3-Mediated genomic instability
BRCA2 plays a critical role in stabilizing stalled replication forks, yet critical gaps remain in understanding how BRCA2 deficiency triggers fork collapse and drives genomic instability. Here, we identify cytidine deaminase APOBEC3B as a key driver of this process. Using a unique uracil-in-DNA probe, we show that BRCA2 loss promotes APOBEC3B-mediated uracil accumulation in single-stranded DNA (U-ssDNA) at stalled forks. These lesions when processed by UNG2 and APE1, trigger fork collapse and release ssDNA fragments into the cytoplasm, activating NF-κB signaling. This in turn upregulates APOBEC3B expression, establishing a self-reinforcing loop that amplifies cytidine deamination at stalled forks and exacerbates genomic instability. Depletion of APOBEC3B, UNG2, or APE1 rescues these defects. Notably, BRCA1-deficient cells do not accumulate U-ssDNA or induce APOBEC3B under replication stress, highlighting a BRCA2-specific vulnerability. Clinically, low APE1 expression correlates with poor survival in patients with BRCA2-mutant tumors, with high APOBEC3 levels further worsening outcomes. Together, our findings establish that replication stress, whether intrinsic or therapy induced, triggers APOBEC3B overexpression and potentially activates an APOBEC3B-driven mutagenic loop in BRCA2-deficient cells. These results position APOBEC3B, UNG2 and APE1 as critical regulators of BRCA2-mutant tumor evolution and therapy resistance.
Authors
- Shailja Pathania (ORCID: https://orcid.org/0000-0001-8974-6420)
- Beáta G. Vértessy (ORCID: https://orcid.org/0000-0002-1288-2982)
- Charles Swanton (ORCID: https://orcid.org/0000-0002-4299-3018)
- Stephen K. Godin (ORCID: https://orcid.org/0000-0002-8726-3254)
- Abby M. Green (ORCID: https://orcid.org/0000-0002-6436-2217)
- Subramanian Venkatesan (ORCID: https://orcid.org/0000-0001-6454-8508)
- Haohui Duan
- Joshua Yang (ORCID: https://orcid.org/0000-0003-2410-7817)
- Nisha Patel
- Jie Chen (ORCID: https://orcid.org/0000-0003-2151-5276)
- Kathy Situ
- Nicolai J. Birkbak (ORCID: https://orcid.org/0000-0003-1613-9587)
- Margaret K. Gillis
- Hajnalka L. Pálinkás (ORCID: https://orcid.org/0000-0003-0761-2440)
- Pratha Rawal
- Silvi Salhotra
- Salome K. Mouliere
- Gabrielle Q. McCloskey
- Basim Naeem
- Muhammad H. Zeb
Institutions
- Aarhus University (DK)
- Washington University in St. Louis (US)
- The Francis Crick Institute (GB)
- Royal London Hospital (GB)
- Cancer Research UK (GB)
- Aarhus University Hospital (DK)
- Budapest University of Technology and Economics (HU)
- University of Massachusetts Boston (US)
- London Cancer (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- University College London (GB)
- HUN-REN Research Centre for Natural Sciences (HU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1038/s41467-025-64578-6
- Citations
- 1
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- U.S. Department of Defense
- Breast Cancer Research Foundation
- Yale University
- Norges Teknisk-Naturvitenskapelige Universitet
- Wellcome Trust
- Francis Crick Institute
- Mark Foundation For Cancer Research
- Cancer Research UK
- National Institute for Health and Care Research
- University College London
- European Commission
- Rosetrees Trust
- Magyar Tudományos Akadémia
- Università degli Studi di Udine
- Innovációs és Technológiai Minisztérium
- National Institutes of Health
- Medical Research Council
- Nemzeti Kutatási, Fejlesztési és Innovaciós Alap
- National Research, Development and Innovation Office