Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors are actively under clinical trials for the treatment of breast and
ovarian cancers that arise due to mutations in BRCA1 and BRCA2. The RAD51 paralog RAD51C has been identified as a breast and
ovarian cancer susceptibility gene. The pathological RAD51C mutants that were identified in
cancer patients are hypomorphic with partial repair function. However, targeting
cancer cells that express hypomorphic mutants of RAD51C is highly challenging. Here, we report that RAD51C-deficient cells can be targeted by a 'synthetic lethal' approach using
PARP inhibitor and this sensitivity was attributed to accumulation of cells in the G2/M and
chromosomal aberrations. In addition, spontaneous hyperactivation of PARP1 was evident in RAD51C-deficient cells. Interestingly, RAD51C-negative cells exhibited enhanced recruitment of non-homologous end joining (NHEJ)
proteins onto
chromatin and this accumulation correlated with increased activity of error-prone NHEJ as well as
genome instability leading to cell death. Notably, inhibition of
DNA-
PKcs or depletion of KU70 or
Ligase IV rescued this phenotype. Strikingly, stimulation of NHEJ by low dose of ionizing radiation (IR) in the
PARP inhibitor-treated RAD51C-deficient cells and cells expressing pathological RAD51C mutants induced enhanced toxicity 'synergistically'. These results demonstrate that
cancer cells arising due to hypomorphic mutations in RAD51C can be specifically targeted by a 'synergistic approach' and imply that this strategy can be potentially applied to
cancers with hypomorphic mutations in other homologous recombination pathway genes.