Journal Article

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

Carreira, Aura, Imyanitov, Evgeny, Cañas, Juan C., Sigurdsson, Stefan, Galarreta, Antonio, Bustos, Maria Rose, Bodvarsdottir, Sigridur Klara, Sridhara, Sreerama Chaitanya, Vincent-Salomon, Anne, Memari, Yasin, Servant, Nicolas, Martin, Charlotte, Gomez-Escudero, Jesus, Baulande, Sylvain, Boucherit, Virginie, Stoppa-Lyonnet, Dominique, Girard, Elodie, Minello, Anna, Nik-Zainal, Serena, Altmeyer, Matthias

2025

Overview

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. Pathogenic BRCA2 truncating variants in heterozygosis drive distinct cancer-linked mechanisms. Here the authors show that one causes PARPi sensitivity and HR loss via haploinsufficiency, while another expresses a truncated protein that rewires transcription by hijacking PCAF, reducing H4 acetylation and NF-κB activity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14 / 14/1 / 14/19 / 38 / 38/23 / 38/39 / 38/91 / 45 / 631/337/149 / 631/337/572 / 631/67/1244 / 82/1 / 82/80 / Acetylation / Acetyltransferase / BRCA2 protein / BRCA2 Protein - genetics / BRCA2 Protein - metabolism / Breast / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / Cell Line, Tumor / Cloning / CRISPR / Epithelial cells / Epithelium / Female / Haploinsufficiency / Histone H4 / Histones - metabolism / Homologous recombination / Humanities and Social Sciences / Humans / Life Sciences / Mice / multidisciplinary / Mutation / NF-kappa B - genetics / NF-kappa B - metabolism / NF-κB protein / Ovarian cancer / Ovarian Neoplasms - genetics / p300-CBP Transcription Factors - genetics / p300-CBP Transcription Factors - metabolism / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Proteins / Science / Science (multidisciplinary) / Sensitivity / Sequestering / Signal Transduction / Statistical analysis / Transcription / Transcription, Genetic / Tumorigenesis / Tumors