BRCA2 deficiency and replication stress drive APOBEC3-Mediated genomic instability

Kathy Situ, Haohui Duan, Stephen K. Godin, Joshua Yang, Gabrielle Q. McCloskey, Basim Naeem, Margaret K. Gillis, Muhammad H. Zeb, Silvi Salhotra, Pratha Rawal, Nisha Patel, Salome K. Mouliere, Jie Chen, Angéla Békési, Hajnalka L. Pálinkás, Subramanian Venkatesan, Abby M. Green, Nicolai J. Birkbak, Beáta G. Vértessy, Charles Swanton and Shailja Pathania ()
Additional contact information
Kathy Situ: University of Massachusetts Boston
Haohui Duan: University of Massachusetts Boston
Stephen K. Godin: University of Massachusetts Boston
Joshua Yang: University of Massachusetts Boston
Gabrielle Q. McCloskey: University of Massachusetts Boston
Basim Naeem: University of Massachusetts Boston
Margaret K. Gillis: University of Massachusetts Boston
Muhammad H. Zeb: University of Massachusetts Boston
Silvi Salhotra: University of Massachusetts Boston
Pratha Rawal: University of Massachusetts Boston
Nisha Patel: University of Massachusetts Boston
Salome K. Mouliere: University of Massachusetts Boston
Jie Chen: University of Massachusetts Boston
Angéla Békési: Műegyetem Rkp. 3
Hajnalka L. Pálinkás: Műegyetem Rkp. 3
Subramanian Venkatesan: University College London Cancer Institute
Abby M. Green: Washington University School of Medicine
Nicolai J. Birkbak: Aarhus University Hospital
Beáta G. Vértessy: Műegyetem Rkp. 3
Charles Swanton: University College London Cancer Institute
Shailja Pathania: University of Massachusetts Boston

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64578-6

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