Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function

Mutations in the N-terminal coiled-coil domain of PALB2 (amino acids 9-44), involved in self-interaction and BRCA1 binding, impair the interaction of PALB2 with BRCA1. Phosphorylation of PALB2 by ATR on serine residue S59 promotes BRCA1-PALB2 interaction and the localization of PALB2 to DNA damage sites. Mutations in the coiled-coil domain can also affect PALB2 self-interaction, recruitment to double-strand break sites, homologous recombination repair, and RAD51 foci formation. PALB2 missense mutants that do not bind to BRCA1 can still be recruited to DNA double-strand break repair (DSBR) sites, probably through interaction with other proteins involved in DSBR, but they are unable to restore efficient gene conversion in PALB2-deficient cells and they render cells hypersensitive to the DNA damaging agent mitomycin C. Some variants in this region are also sensitive to PARP inhibitors.

Summary from Reactome (R-HSA-9704331), read 2026-09-23.