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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Arafat Khan,
  • Justin F. Lim,
  • Natalie Lo,
  • Jinal A. Patel,
  • John Haley,
  • Hyungjin Kim

摘要

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.