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