{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Khan A"],"funding":["NCI NIH HHS","U.S. Department of Health & Human Services | National Institutes of Health (NIH)","NIGMS NIH HHS"],"pagination":["1683"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12647206"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["8(1)"],"pubmed_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."],"journal":["Communications biology"],"pubmed_title":["TIPIN coordinates ATM-dependent checkpoint and NF-κB signaling to counteract DNA replication damage from topoisomerase inhibition."],"pmcid":["PMC12647206"],"funding_grant_id":["R01CA285515","R01 CA285515","R01GM144399","R01 GM144399"],"pubmed_authors":["Patel JA","Lo N","Kim H","Lim JF","Khan A","Haley J"],"additional_accession":[]},"is_claimable":false,"name":"TIPIN coordinates ATM-dependent checkpoint and NF-κB signaling to counteract DNA replication damage from topoisomerase inhibition.","description":"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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Nov","modification":"2026-06-05T16:43:11.387Z","creation":"2026-05-18T03:13:08.25Z"},"accession":"S-EPMC12647206","cross_references":{"pubmed":["41291151"],"doi":["10.1038/s42003-025-09084-7"]}}