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While endogenous inhibitors (EndoGI) control EndoG in lower organisms, no such EndoGI has been identified in mammalian cells. Due to the structural similarity of EndoGI from\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    to the C-terminus (Ct) of human Ku80, we perform immunoprecipitation, surface plasmon resonance analysis and 3D molecular modeling, revealing binding of human EndoG to Ku80-Ct putatively between amino acid 110\u2013184. Docking modeling predicts EndoGI-like peptides clustering around residues 686-707 of Ku80. Our experimental studies provide evidence that Ku80-Ct and 28-mer peptide Ku3 reduce\n                    <jats:italic>MLL<\/jats:italic>\n                    bcr breakage after doxorubicin treatment independently of DNA-PK activity. Proximity ligation and single molecule tracking studies show that Ku3 antagonizes Ku80-EndoG association and modulates chromatin-binding of EndoG. Such\n                    <jats:italic>MLL<\/jats:italic>\n                    bcr protection blocks EndoG\u00b4s pro-tumorigenic functions without limiting cytotoxicity, pursued for co-treatments that reduce secondary leukemia, a severe side effect of chemotherapy.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-72034-2","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:55:03Z","timestamp":1776387303000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Discovery of an Endonuclease G-inhibitory Ku80-peptide protecting against leukemogenic rearrangements at the MLL breakpoint cluster"],"prefix":"10.1038","volume":"17","author":[{"given":"Julia","family":"Eberle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5115-1779","authenticated-orcid":false,"given":"Ahmed","family":"Salem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Reisser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasser B.","family":"Ruiz-Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9832-3534","authenticated-orcid":false,"given":"Yasser","family":"Almeida-Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Gole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2991-5223","authenticated-orcid":false,"given":"Melanie","family":"Rall-Scharpf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9661-2148","authenticated-orcid":false,"given":"Jessica","family":"Angulo-Capel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3748-710X","authenticated-orcid":false,"given":"Thomas","family":"Monecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9211-5803","authenticated-orcid":false,"given":"Elsa","family":"Sanchez-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1900-600X","authenticated-orcid":false,"given":"J. 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