Résumé
Genome integrity preservation warrants cell fitness, therefore cells challenged with genotoxic stress activate the DNA Damage Response (DDR) to coordinate cell cycle arrest with DNA repair. We explored whether lipid droplet (LD) biology is important for genome integrity preservation. We found that genotoxic stress triggers the birth of LD that serve as a sink for sterols (*). Sterol removal from the ER dampens OSBP1 activity, a machine that translocates (thus depletes) Phosphatidyl-Inositol-4-P (PI4P) from the Golgi. We found that the DDR master kinase ATM, which signals DNA double strand breaks in the nucleus, binds this pool of Golgi-stabilized PI4P, in agreement with its evolutionary belonging to a PIP kinase family. This ATM binding to Golgi-resident PI4P acts as a lock, titrating it away from its nuclear duties, thus attenuating the DDR. DDR attenuation is important to authorize the latter steps of DNA repair and to resume cell cycling. Reciprocally, either preventing sterol esterification towards LD, boosting OSBP1 activity, or stimulating PI4P hydrolysis, all trigger PI4P consumption, subsequently free ATM, and sustain a hyper-activated DDR. We bring the unprecedented notion that manipulating a lipid axis can directly impact on the degree of genome integrity. This challenges the current view of the DDR as a signaling cascade exclusively controlled by proteins, placing LD as a key organelle ruling adaptation to DNA damage.