Genetic instability is a major risk leading to the development of cancers, birth defects, neurological disorders, premature aging, and death. DNA double-strand breaks (DSBs) are a major source of genetic instability, particularly genomic rearrangements. DSBs are also used in various physiological processes aimed at generating genetic diversity. Therefore, controlling DSB repair is a key issue: it must maintain genome stability, allowing genetic diversity while avoiding genetic instability.
In the face of genotoxic stress, the DNA Damage Response (DDR) maintains genome stability by coordinating a network of metabolic pathways, including DNA damage signaling and repair. It is noteworthy that defects in the DDR lead to genetic instability, premature aging, and a predisposition to cancer. In particular, the MRN complex (MRE11-RAD50-NBS1) is recruited very early to DSB sites and is essential for the full activation of ATM (Ataxia telangectasia mutated) signaling, which plays a central role in DSB signaling and repair.

Protein kinase B (PKB, also known as AKT1) is an oncogenic kinase and one of the most frequently deregulated oncogenes in various cancers. Notably, AKT1/PKB is upregulated in a high percentage of sporadic breast and ovarian cancers. Since most mutations predisposing to hereditary breast or ovarian cancers affect genes controlling DDR, this raises the question of whether AKT1/PKB has a direct impact on genomic instability.In this study, the researchers show that increased AKT1/PKB induces genetic instability and chromosomal rearrangements in various types of cell lines, both cancerous and non-cancerous, using various biological assays and analyzing breast cancer genomic databases in cBioPortal. The researchers reveal the molecular mechanisms by which AKT1/PKB actively promotes genetic instability: AKT1/PKB phosphorylates MRE11 at three sites on the protein, which promotes the assembly of the MRE11-RAD50-NBS1 (MRN) complex, enhancing ATM-mediated DSB signaling and DNA end-joining (EJ) repair. This hyperstimulation of signaling and repair ultimately leads to intra- and interchromosomal genomic rearrangements (translocations, deletions, and inversions). These results reveal a novel role for AKT1/PKB in DSB signaling and repair, mediated by MRE11 phosphorylation, but whose hyperactivation leads to genetic instability.
Several cases of MRE11 phosphorylations have been described, by different kinases and on different residues. But so far, all these MRE11 phosphorylations have been shown to reduce MRE11 activity by decreasing its affinity for DNA and the recruitment of ATM to damaged sites. It has been proposed that these phosphorylations would control the mechanism(s) of deactivation of the MRN complex on DNA and DSB signaling. Here, the researchers identify the first situation in which MRE11 phosphorylation (here by AKT1/PKB) does not antagonize the MRE11/ATM axis but, on the contrary, stimulates its activity in DSB signaling and repair, at the cost of increased genetic instability.
 

These observations are consistent with the high level of genomic instability observed in tumors characterized by AKT1/PKB overexpression in the Cancer Genome Database (cBioportal) and provide a molecular explanation for the radiation resistance observed in AKT1/PKB-positive tumors. Indeed, DSB repair by EJ is a double-edged sword. On the one hand, it is essential for maintaining genome integrity and radiation resistance, but on the other hand, it can generate genetic instability by EJ of distant DSBs, leading to translocations, deletions, inversions, and chromosomal fusions. Here, we show that EJ activation by AKT1/PKB induces genomic rearrangements and chromosomal fusions. While it has long been known that defects in the DDR network lead to genomic instability, the present data show that, in a mirror effect, stimulation of DSB signaling and repair via ATM axis hyperstimulation (here via the AKT1/PKB kinase) also promotes genomic instability. This underscores the importance of precisely controlling these subtle balances.

These results identify a potential novel pharmacological target (MRE11) to optimize therapeutic strategies for AKT1/PKB-positive tumors, potentially sensitizing them to therapies based on genotoxic treatments, including radiotherapy.
In conclusion, these data reveal a new mechanism generating genome instability: the stimulation of JE that contributes to the generation of chromosomal rearrangements. In addition, they position AKT1/PKB as a key apical regulator of the DNA CBD response. More generally, these data show that, similar to the shortcomings of DDR, increased CBD signaling and repair (here by AKT1/PKB) also promotes genomic instability, highlighting the importance of precise control of DDR equilibria.

Reference

Genome rearrangements induced by the stimulation of end-joining of DNA double strand breaks through multiple phosphorylation of MRE11 by the kinase PKB/AKT1. 
Guirouilh-Barbat J, Boueya IL, Gelot C, Pennarun G, Granotier-Beckers C, Dardillac E, Yu W, Lescale C, Rass E, Ariste O, Siaud N, Renouf B, Millet A, Puget N, Bertrand P, de la Grange P, Brunet E, Deriano L, Lopez BS. Nucleic Acids Res. 2025 Jun 6;53(11):gkaf468. doi: 10.1093/nar/gkaf468. PMID: 40479710