Résumé
We aim at creating awareness of the importance and potential of considering the lipid dimension in the field of genome integrity, otherwise populated with studies exclusively considering nucleic acid-protein interactions. We recently discovered that the signaling and repair of DNA double strand breaks, lethal lesions in the genetic material, is controlled by a sterol-phosphoinositide loop necessitating the formation of sterol-rich cytoplasmic lipid droplets. Briefly, in response to DNA breaks, sterols are stored within cytoplasmic lipid droplets, which lowers their level of sterols in the endoplasmic reticulum (ER). This restricts their exchange against phosphatidylinositol-4-phosphate (PI4P) at the membrane contact sites between ER and Golgi. PI4P stabilized this way at the Golgi titrates the nuclear pool of a protein essential to monitor DNA breaks repair, the kinase ATM. Depending on how this sterol-PI4P loop is modulated, we demonstrated that we can alter ATM presence (and activity) on DNA, and thus the DNA repair process. At present, we explore if similar or alternative lipid circuits operate when the DNA lesions the cell is confronted to are of a different nature. In particular, when the duplication of DNA is compromised, a phenomenon termed "replicative stress". Our findings delineate an interesting picture in which different DNA lesions elicit different fates for sterol moieties… and different lipid droplets populations. More importantly, lipid droplet manipulation has the power of dictating alternative fates for the damaged DNA molecules, revealing an unprecedented control of lipid storage onto genome integrity.