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

Area of Science:

• Genetics
• Cancer Biology
• Molecular Oncology

Background:

• Germline BRCA2 mutations predispose to breast and ovarian cancers.
• Tumorigenesis is often linked to biallelic BRCA2 inactivation, but haploinsufficiency is also implicated.

Purpose of the Study:

• To investigate the functional consequences of heterozygous BRCA2 truncating variants in breast epithelial cells.
• To elucidate the mechanisms underlying BRCA2 haploinsufficiency and dominant-negative effects.

Main Methods:

• Modeling pathogenic BRCA2 variants in non-tumorigenic breast epithelial cells.
• Assessing homologous recombination (HR) efficiency and PARP inhibitor (PARPi) sensitivity.
• Investigating protein interactions, transcriptional rewiring, and signaling pathway modulation.

Main Results:

• One BRCA2 variant led to haploinsufficiency, causing PARPi sensitivity and reduced HR.
• A second variant produced a truncated protein with dominant-negative activity, forming oligomers with BRCA2 and sequestering PCAF.
• This interaction suppressed NF-κB signaling and altered epithelial cell migration.

Conclusions:

• BRCA2 haploinsufficiency can contribute to tumorigenesis.
• A novel BRCA2-PCAF axis regulates NF-κB signaling, which is disrupted by a pathogenic BRCA2 variant.
• Findings reveal new therapeutic targets and mechanisms in BRCA2-associated cancers.