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DNA double-strand break (DSB) is a highly toxic lesion, jeopardizing genome stability. Using cytogenetic and differential exome sequencing, we show here that upregulation of the kinase PKB\/AKT1 leads to genomic rearrangements and chromosome fusions. By combining various approaches, at the genome scale and at precise loci, we show that PKB\/AKT1 stimulates DSB end-joining, leading to inter- and intrachromosomal genomic rearrangements. The MRE11\u2013RAD50\u2013NBS1 (MRN) complex plays an essential role in the early steps of DSB signaling\/repair. We show here that PKB\/AKT1 favors the assembly of MRN, leading to the stimulation of DSB signaling via the MRE11\/ATM axis. We identify MRE11 as a phosphorylation effector of PKB\/AKT1 and reveal several sites whose phosphorylation is required for PKB-mediated stimulation of DSB end-joining and chromosome fusions. These data reveal that PKB\/AKT1 actively promotes genetic instability by increasing the efficiency of DSB end-joining through MRE11 phosphorylation on these sites. These results highlight that not only a defect of DSB signaling\/repair but also its stimulation, can lead to genome rearrangements and underline the importance of a precise regulation of the DNA damage response to maintain genome stability.<\/jats:p>","DOI":"10.1093\/nar\/gkaf468","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T19:41:14Z","timestamp":1749238874000},"source":"Crossref","is-referenced-by-count":1,"title":["Genome rearrangements induced by the stimulation of end-joining of DNA double strand breaks through multiple phosphorylation of MRE11 by the kinase PKB\/AKT1"],"prefix":"10.1093","volume":"53","author":[{"given":"Jos\u00e9e","family":"Guirouilh-Barbat","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Paris Cit\u00e9 , INSERM U1016, UMR 8104 CNRS, Institut Cochin, 24 rue du Faubourg St. Jacques, 75014 Paris ,","place":["France"]},{"name":"CNRS UMR 8200, Institut de Canc\u00e9rologie Gustave-Roussy, Universit\u00e9 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