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Exposure to damaging agents induced the interaction of NEMO with a preformed ATM-IKK\u03b1 complex, which was required to target active ATM and IKK\u03b1 to chromatin for efficient DNA damage repair but not for activating ATM. Recognition of damaged DNA by the IKK\u03b1-NEMO-ATM complex was facilitated by the interaction between NEMO and histones and depended on the ADP ribosylation of histones by the enzyme PARP1. NEMO-deficient cells showed increased activity of the kinase ATR, and inhibition of ATR potentiated the effect of chemotherapy in cells lacking NEMO or IKK\u03b1. Bioinformatic analysis of colorectal cancer datasets demonstrated that the expression of genes encoding IKK\u03b1, NEMO, and ATM correlated with poor patient prognosis, suggesting that the mechanism linking these three elements may be clinically relevant.<\/jats:p>","DOI":"10.1126\/scisignal.adr0128","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T17:58:31Z","timestamp":1741715911000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["NEMO is essential for directing the kinases IKK\u03b1 and ATM to the sites of DNA damage"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6783-5166","authenticated-orcid":true,"given":"Josune","family":"Alonso-Mara\u00f1\u00f3n","sequence":"first","affiliation":[{"name":"Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, 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Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leire","family":"Uraga","sequence":"additional","affiliation":[{"name":"Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Hooper","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Wisconsin Institutes for Medical Research, Madison, WI 53705, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6506-7714","authenticated-orcid":true,"given":"Eduard","family":"Sabid\u00f3","sequence":"additional","affiliation":[{"name":"Proteomics Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona 08003, Spain."},{"name":"Proteomics Unit, 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