PARP1 trapping activates ATM-mediated NF-κB signaling independent of replication in response to TOP1 blockade.

The NF-κB signaling pathway is a key driver of inflammation and can be activated by many genotoxic stresses. Yet, the mechanisms by which different types of DNA damage trigger NF-κB remain poorly understood. In this study, we find that NF-κB activation by topoisomerase 1 (TOP1) inhibition is strongly increased when cells are treated in combination with PARP inhibitors. Mechanistically, we demonstrate that TOP1 inhibition activates ATM-mediated NF-κB signaling through two distinct pathways: a replication-dependent pathway triggered by replication fork collapse and a replication-independent pathway revealed upon PARP1 inhibition. We further show that PARP1 enzymatic activity is not required to suppress NF-κB signaling after TOP1 inhibition during the replication-independent pathway. Instead, PARP inhibitors trap PARP1 at DNA lesions, thereby blocking repair and promoting ATM-dependent NF-κB signaling, mimicking the cell response to TDP1 depletion. These findings reveal an unexpected role for PARP1 as an NF-κB activator when trapped at DNA lesions induced by TOP1 inhibition, providing a therapeutic opportunity to use PARP inhibitors to enhance inflammatory responses and potentially improve the efficacy of TOP1-targeted cancer therapies.