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TIPIN coordinates ATM-dependent checkpoint and NF-κB signaling to counteract DNA replication damage from topoisomerase inhibition
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TIPIN coordinates ATM-dependent checkpoint and NF-κB signaling to counteract DNA replication damage from topoisomerase inhibition
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Journal Article
TIPIN coordinates ATM-dependent checkpoint and NF-κB signaling to counteract DNA replication damage from topoisomerase inhibition
2025
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 13/89
/ 14/63
/ 38/109
/ 38/77
/ 82/58
/ 96/95
/ Adaptor Proteins, Signal Transducing - metabolism
/ Ataxia
/ Ataxia Telangiectasia Mutated Proteins - genetics
/ Ataxia Telangiectasia Mutated Proteins - metabolism
/ Biomedical and Life Sciences
/ Cancer
/ DNA Replication - drug effects
/ Homology
/ Humans
/ Kinases
/ Proteins
/ Topoisomerase Inhibitors - pharmacology
/ Trans-Activators - metabolism
/ Yeast
