DNA repair: an essential balance in the stability of the genome
Genetic instability is a factor associated with the appearance and development of cancers and other serious illnesses. Among the most serious lesions are double -strand DNA breaks (CDB). CDBs are also used in different physiological processes which aim to generate genetic diversity, especially when establishing the immune repertoire or meiosis. Consequently, control of the repair of CDBs is an essential issue: it must maintain the stability of the genome, by allowing genetic diversity, but by avoiding genetic instability.
Faced with genotoxic stresses, cells activate a complex mechanism: the response to DNA damage (DDR: DNA Damage Response) which orchestrates the signaling and repair of DNA. Any failure in the DDR can cause genetic instability, premature aging and a predisposition to cancer. A central actor in this response is the MRN (MRE11-RAD50-NBS1) complex which intervenes very early on to activate signaling via ATM kinase, essential for coordination of CDB repair.
The Protein Kinse B (AKT1/PKB) is a kinase involved in many cell signs. It is frequently deregulated in various cancers, especially in the sporadic forms of breast and ovary cancer, where its expression is often increased.
Given that many mutations involved in hereditary cancers in the breast or the ovary affect DDR genes, scientists have questioned the impact of AKT1/PKB on the stability of the genome.
An unprecedented mechanism: hyperactivation of repair leads to genomic instability
In this study, published in the journal Nucleic Acids Research, They show that the increase in AKT1/PKB activity induces genetic instability and chromosomal rearrangements, observed in several cellular lines, cancer or not, with different biological tests and by the analysis of genomic databases from CBIOPTAL on breast cancer.
Scientists have identified a mechanism by which AKT1/PKB actively promotes genetic instability. By phosphorying the protein MRE11 On three sites, AKT1/PKB promotes the assembly of the MRN complex, stimulating the ATM signaling and the repair of breaks via the religature of the DNA extremities (end-jeing, EJ).
However, this hyperactivation of repair is not without consequences: it generates intra and inter-chromosomal rearrangements (translocations, deletions, inversions), source of instability.
This observation contrasts with previous works where the phosphorylations of MRE11, by different kinases and on different sites, were rather associated with an inhibition of its activity, in particular by reducing its affinity to DNA and the recruitment of ATM on damaged sites. Here, this is the first time that MRE11 phosphorylation has stimulated signaling and repair on the contrary, but at the cost of increased instability.
A new therapeutic target
The results are consistent with the high genomic instability observed in the overexpressing tumors AKT1/PKB in the databases of the Cancer of Cancer (Cbioportal). They also provide A molecular explanation for radiation resistance observed in the AKT1/PKB-Postive tumors.
Indeed, the repair of CDB Constitutes a double -edged sword: although it is essential to maintain the integrity of the genome and resistance to radiation, it can also cause genomic rearrangements by connecting the distant breaks between them.
Thus, this study shows that the hyperactivation of the DDR, and not its simple failure, can also generate genetic instability. This underlines the importance of strict balance in the DNA signaling and repair processes.
Finally, this work highlights MRE11 as a new potential therapeutic target, which could be exploited to raise awareness among AKT1/PKB-Postifies tumors of genotoxic treatments, such as radiotherapy.