A recurrent pathogenic BRCA2 truncating variant reveals a role for BRCA2-PCAF complex in modulating NF-κB-driven transcription

Abstract

Germline monoallelic truncating mutations in BRCA2, a key mediator of homologous recombination (HR), predispose individuals to breast and ovarian cancer. Tumorigenesis is typically attributed to biallelic inactivation, yet evidence suggests haploinsufficiency can suffice in some contexts. We model two pathogenic BRCA2 truncating variants in heterozygosis in non-tumorigenic breast epithelial cells. One variant is not expressed and confers PARP inhibitor (PARPi) sensitivity and reduced HR, indicating haploinsufficiency. In contrast, the other produces a truncated protein that rewires transcription in cells and tumors. Mechanistically, this truncated product acts as a dominant negative by forming abnormal oligomers with full-length BRCA2 and sequestering the PCAF acetyltransferase. This interaction reduces global histone H4 acetylation and suppresses NF-κB transcriptional activity, ultimately altering epithelial migration. Our findings reveal a BRCA2-PCAF axis that modulates NF-κB signaling, a process co-opted by a recurrent BRCA2 pathogenic variant.

Affiliated Institutions

• University of Iceland IS
• Université Paris Cité FR
• École Nationale Supérieure des Mines de Paris FR
• Inserm FR
• Institut Curie FR
• Université Paris-Saclay FR
• Centro de Biología Molecular Severo Ochoa ES
• University of Zurich CH
• University of Cambridge GB
• Institute of Oncology NN Petrov RU
• Université Paris Sciences et Lettres FR
• Cancer Research UK Cambridge Center GB

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