Stephane MANENTI
investiguateurs associes : Anne CAMMAS et stefania millevoi
DNA damage response regulators
in post-transcriptional control
BACKGROUND
Many therapeutic treatments are based on the use of genotoxic drugs that induce a DNA damage response (DDR) in proliferating cancer cells. The DDR (including cell cycle arrest, DNA repair, transcriptional adjustments and apoptosis) may be responsible for resistance to genotoxic drugs as well as incomplete therapeutic response in different cancer types. Therefore, several pharmacological inhibitors of the DDR have been developed and proposed as potential therapeutic tools in different cancers. In the last decade, there is considerable evidence that RNA regulation by RNA-binding proteins (RBPs) is a central player in the DDR.
ACHIEVEMENTS
S. Manenti investigated the expression, regulatory mechanisms, and novel functions of key players in the DNA damage response and cell cycle (CHK1 and CDC25A), and their importance in models of Acute Myeloid Leukemia (AML) (Adam, K., (2018) J.Cell Sci.; David, L., (2016) Sci. Signal.; Cartel, M., (2021) Leukemia). S. Millevoi and A. Cammas pioneered a concept that key DDR proteins could directly impact the RNA metabolism, demonstrating that the DNA repair protein Ku70/Ku80 controls TP53 translation via its binding to a stem loop structure located in the 5’UTR of the mRNA (Lamaa, A., (2016) EMBO Rep.).
ONGOING/FUTURE PROJECTS
A classical view of the DDR proposes that cellular processes are concomitant with post-transcriptional control of DDR protein expression, enabling feedback loops necessary for precise regulation of the survival/death balance. We aim to explore a new concept suggesting that DDR “sensor” and “transducer” proteins directly impact post-transcriptional gene expression, thereby adjusting the cellular response to DNA threats. Based on our previous work (Lamaa, A. (2016) EMBO Rep.) as well as unpublished data, we will focus on studying i) the DNA repair factor Ku70/80; ii) the two cell cycle players, CHK1 and CDC25A.
