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

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.

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Publication Details

Journal
Nature Communications
Published
2025-12-10
DOI
https://doi.org/10.1038/s41467-025-67209-2
Primary Topic
BRCA gene mutations in cancer
Type
article
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article

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

Antonio Galarreta, Anna Minello, Elodie Girard, Anne Vincent‐Salomon et al.
Nature Communications
BRCA gene mutations in cancer
article

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

Antonio Galarreta, Anna Minello, Elodie Girard, Anne Vincent‐Salomon, Stefán Sigurðsson, Nicolas Servant, Maria Rose Bustos, Virginie Boucherit, Sree Rama Chaitanya Sridhara, Charlotte Martin, Yasin Memari, Serena Nik‐Zainal, Sylvain Baulande, Aura Carreira, Dominique Stoppa‐Lyonnet, Matthias Altmeyer, Juan C. Cañas, Jesús Gómez-Escudero, Sigríður Klara Böðvarsdóttir, Evgeny Imyanitov
article en

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.

Nature CommunicationsVol. 16(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), University of Iceland (IS), University of Zurich (CH), Université Paris Cité (FR), University of Cambridge (GB), Université Paris Sciences et Lettres (FR), Université Paris-Saclay (FR), Cancer Research UK Cambridge Center (GB), Institute of Oncology NN Petrov (RU), Centro de Biología Molecular Severo Ochoa (ES), Icelandic Cancer Society (IS), Universidad Autónoma de Madrid (ES), École Nationale Supérieure des Mines de Paris (FR), Institut Curie (FR)
Openalex Percentile: Top 59%
BRCA gene mutations in cancer
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