Minello, A.; Gomez-Escudero, J.; Sridhara, S. C.; Martin, C.; Girard, E.; Canas, J. C.; Memari, Y.; Bustos, M. R.; Galarreta, A.; Boucherit, V.; Imyanitov, E.; Bodvarsdottir, S. K.; Baulande, S.; Vincent-Salomon, A.; Servant, N.; Altmeyer, M.; Sigurdsson, S.; Stoppa-Lyonnet, D.; Nik-Zainal, S.; Carreira, A.

Germline monoallelic truncating mutations in BRCA2, a critical mediator of homologous recombination (HR), predispose individuals to breast and ovarian cancer. While tumorigenesis is usually attributed to biallelic inactivation, emerging evidence suggests that haploinsufficiency may suffice in certain contexts. To investigate this, we recreated two BRCA2 pathogenic truncating variants in heterozygosis in non-tumorigenic breast epithelial cells. Cells carrying a truncating mutation that was not produced prompted sensitivity to PARP inhibitors (PARPi) and reduced the HR capacity indicating haploinsufficiency. Surprisingly, the other variant was expressed as a truncated product and prompted a transcriptional rewiring. Mechanistically, the truncated BRCA2 product formed abnormal oligomers with full-length BRCA2 and bound to the PCAF acetyltransferase, sequestering it. This led to reduced global histone H4 acetylation and decreased NF-{kappa}B transcriptional activity, ultimately impairing epithelial cell migration--a process also altered in tumors. Our findings uncover a previously unrecognized BRCA2-PCAF axis that modulates NF-{kappa}B-driven transcriptional program, a process that is co-opted by a recurrent BRCA2 pathogenic variant.