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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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

摘要

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.