Tumor cell intrinsic dsRNA innate immune response triggered by PARP inhibitor is compromised in BRCA1 deficient breast cancer by repressing IRF3

Recent evidence shows that efficacy of DNA damage drugs depends on two aspects, DNA repair signaling and immune response. Applying a functional proteomics approach, we find that the function of spliceosome is perturbed by PARP inhibitors via enhancing interaction between PARP1 and SF3B1, a key factor of spliceosome.

We demonstrate that differential alternative spliced mRNA and accumulation of double strand RNA (dsRNA) are induced by perturbation of spliceosome upon PARP inhibitors treatment, resulting in triggering dsRNA antiviral mimicry innate immune response. Moreover, we identify a novel function of BRCA1, through which BRCA1 regulates innate immune response leading to compromising of the innate immune signaling by downregulation of IRF3 in BRCA1 deficient breast cancer cells, which reduces the sensitivity to PARP inhibitors and causes intrinsic resistance.