Guirouilh-Barbat Josée, Boueya Iman Litchy, Gelot Camille, Pennarun Gaëlle, Granotier-Beckers Christine, Dardillac Elodie, Yu Wei, Lescale Chloé, Rass Emilie, Ariste Olivier, Siaud Nicolas, Renouf Benjamin, Millet Armel, Puget Nadine, Bertrand Pascale, de la Grange Pierre, Brunet Erika, Deriano Ludovic, Lopez Bernard S
Université de Paris Cité, INSERM U1016, UMR 8104 CNRS, Institut Cochin, 24 rue du Faubourg St. Jacques, 75014 Paris, France.
CNRS UMR 8200, Institut de Cancérologie Gustave-Roussy, Université Paris-Saclay, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
Nucleic Acids Res. 2025 Jun 6;53(11). doi: 10.1093/nar/gkaf468.
Genetic instability is a major hazard threatening the fate of cells and ultimately of organisms. 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-RAD50-NBS1 (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.
基因不稳定是威胁细胞乃至生物体命运的主要危险因素。DNA双链断裂（DSB）是一种剧毒损伤，会危及基因组稳定性。通过细胞遗传学和差异外显子组测序，我们在此表明激酶PKB/AKT1的上调会导致基因组重排和染色体融合。通过在基因组规模和精确位点结合多种方法，我们表明PKB/AKT1刺激DSB末端连接，导致染色体间和染色体内基因组重排。MRE11-RAD50-NBS1（MRN）复合物在DSB信号传导/修复的早期步骤中起重要作用。我们在此表明PKB/AKT1有利于MRN的组装，导致通过MRE11/ATM轴刺激DSB信号传导。我们将MRE11鉴定为PKB/AKT1的磷酸化效应物，并揭示了几个位点，其磷酸化是PKB介导的DSB末端连接和染色体融合刺激所必需的。这些数据表明，PKB/AKT1通过增加这些位点上MRE11磷酸化导致的DSB末端连接效率，积极促进基因不稳定。这些结果强调，不仅DSB信号传导/修复缺陷，而且其刺激都可导致基因组重排，并突显了精确调节DNA损伤反应以维持基因组稳定性的重要性。
