TIPIN coordinates ATM-dependent checkpoint and NF-κB signaling to counteract DNA replication damage from topoisomerase inhibition
Year: 2025
Type: article
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. Together, our study defines TIPIN as a master regulator of ATM-dependent DSB repair and NF-κB signaling. We propose that targeting MDC1, a key effector of ATM-TIPIN signaling, acts as a chemosensitizer that suppresses therapy-induced senescence and augments the effectiveness of genotoxic therapy. Identification and characterization of the DNA damage response and NF-κB signaling coordinated by the replication machinery offers a strategy to target its regulatory axis as a chemosensitizer for the topoisomerase inhibitor cancer therapy.
Source: Communications Biology
Authors: Arafat Khan, Justin F. Lim, Natalie Lo, Jinal A. Patel, John Haley, Hyungjin Kim
Institutions: Stony Brook University, State University of New York
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
OpenAlex ID: W4416667996