TIPIN coordinates ATM-dependent checkpoint and NF-κB signaling to counteract DNA replication damage from topoisomerase inhibition.

ABSTRACT: ATM is an apical kinase that governs cellular responses to DNA replication-associated double strand breaks (DSBs) accumulated by the topoisomerase inhibitor anti-cancer therapy. Here we identify that TIPIN, a major constituent of the fork protection complex in the replisome, plays a key role in coordinating ATM signaling tied to DNA replication stress. We demonstrate that TIPIN amplifies ATM signaling to promote DNA end resection and homology-directed repair. TIPIN itself is phosphorylated by ATM, which is required for the recruitment of MDC1 to stalled forks to promote ATM-dependent NF-κB activation. Inhibition of the NF-κB pathway by MDC1 depletion impairs upregulation of anti-apoptotic regulator c-FLIP, thus potentiating caspase-8 activation and cytotoxicity of topoisomerase inhibition.

SUBMITTER: Khan A 

PROVIDER: S-EPMC12647206 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature