Patient-derived separation-of-function mutations reveal specific role for BRCA1 coiled coil domain in genome stability.

BRCA1, PALB2

Separation-of-function variant in the BRCA1 coiled coil domain (L1407P equivalent): loss of the PALB2 interaction, increased base substitution mutagenesis, preserved double-strand break repair

Using a panel of isogenic chicken DT40 cell lines, the authors compared the main BRCA1 protein domains and common BRCA1 founder mutations for their role in genome stability and DNA repair. Whole genome sequencing of cell clones showed that the L1407P-equivalent coiled coil domain variant is a separation-of-function mutant: it increases base substitution mutagenesis without deletions or large-scale genomic instability, as it remains proficient in repairing double-strand breaks and promoting sister chromatid exchanges. The BRCA1 coiled coil domain mediates the interaction with PALB2, and PALB2 coiled coil domain mutations likewise mainly affect base substitution mutagenesis. In contrast, truncating and missense mutations in the RING and BRCT domains impair all BRCA1 functions, inducing larger deletions and rearrangements typical of BRCA1 loss. PARP inhibitor sensitivity is marginal in coiled coil domain mutants and instead correlates with deletion mutagenesis, degradation of stalled replication forks and impaired RAD51 loading after topoisomerase I inhibition.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The clinical interest is indirect but real: a BRCA1 variant can impair one function while sparing others, which a functional assay focused solely on double-strand break repair may fail to capture. The marginal PARP inhibitor sensitivity of coiled coil domain mutants questions extrapolating therapeutic response to all carriers, but these data come from an avian model and need confirmation in human cells and in patients. The abstract does not specify the clinical classification of the L1407P variant.

Analysis by Dr Thibaut Benquey