Genome rearrangements induced by the stimulation of end-joining of DNA double strand breaks through multiple phosphorylation of MRE11 by the kinase PKB/AKT1
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.
Authors
- Erika Brunet (ORCID: https://orcid.org/0000-0002-1726-4673)
- Pierre de la Grange (ORCID: https://orcid.org/0000-0001-6361-1878)
- Christine Granotier (ORCID: https://orcid.org/0000-0003-1063-1159)
- Nadine Puget (ORCID: https://orcid.org/0000-0003-4046-737X)
- Chloé Lescale (ORCID: https://orcid.org/0000-0003-0622-1149)
- Olivier Ariste
- Bernard S. López (ORCID: https://orcid.org/0000-0001-5088-0155)
- Armêl R. Millet
- Camille Gelot
- Pascale Bertrand (ORCID: https://orcid.org/0000-0002-9019-742X)
- Elodie Dardillac (ORCID: https://orcid.org/0000-0002-2069-8309)
- Josée Guirouilh‐Barbat (ORCID: https://orcid.org/0000-0002-8845-7333)
- Nicolas Siaud
- Gaëlle Pennarun (ORCID: https://orcid.org/0000-0001-9881-9345)
- Ludovic Deriano (ORCID: https://orcid.org/0000-0002-9673-9525)
- Emilie Rass (ORCID: https://orcid.org/0000-0003-4890-7771)
- Wei Yu (ORCID: https://orcid.org/0000-0002-1777-5254)
- Benjamin Renouf
- Iman Litchy Boueya
Institutions
- Délégation Paris 5 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Sorbonne Paris Cité (FR)
- CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR)
- Immunité et Cancer (FR)
- CEA Paris-Saclay (FR)
- Institut Cochin (FR)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1093/nar/gkaf468
- Citations
- 1
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Institut National Du Cancer