# Sterol control onto the fate of DNA repair intermediates

María Moriel-Carretero

► To cite this version:

María Moriel-Carretero. Sterol control onto the fate of DNA repair intermediates. Roles of Lipids in Nuclear Homeostasis and Genome Stability, The Company of Biologists, Oct 2024, Hertfordshire, United Kingdom. **hal-05349609**

HAL Id: hal-05349609

https://hal.science/hal-05349609v1

Submitted on 5 Nov 2025

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Sterol control onto the fate of DNA repair intermediates

María Moriel-Carretero

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. Briefly, in response to DNA breaks, the esterification and storage of sterols within cytoplasmic lipid droplets is launched, with the immediate consequence of lowering the level of sterols in the endoplasmic reticulum (ER). This restricts the possible exchange of sterols against phosphatidyl-inositol-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 have explored 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". An interesting picture starts to emerge in which different DNA lesions elicit different fates for sterol moieties... and in which sterol manipulation has the power of dictating alternative fates for the damaged DNA molecules.