A sterol‐PI(4)P exchanger modulates the Tel1/ATM axis of the DNA damage response

Upon DNA damage, cells activate the DNA damage response (DDR) to coordinate proliferation and DNA repair. Dietary, metabolic, and environmental inputs are emerging as modulators of how DNA surveillance and repair take place. Lipids hold potential to convey these cues, although little is known about how. We observed that lipid droplet (LD) number specifically increased in response to DNA breaks. Using Saccharomyces cerevisiae and cultured human cells, we show that the selective storage of sterols into these LD concomitantly stabilizes phosphatidylinositol‐4‐phosphate (PI(4)P) at the Golgi, where it binds the DDR kinase ATM. In turn, this titration attenuates the initial nuclear ATM‐driven response to DNA breaks, thus allowing processive repair. Furthermore, manipulating this loop impacts the kinetics of DNA damage signaling and repair in a predictable manner. Thus, our findings have major implications for tackling genetic instability pathologies through dietary and pharmacological interventions. Synopsis How can metabolic and environmental cues modulate the DNA damage response (DDR)? Here, the master DDR kinase Tel1/ATM is found to bind phosphatidylinositol‐4‐phosphate (PI(4)P) at the Golgi, altering its availability in the nucleus and impacting the kinetics, intensity, and persistence of the response to DNA double‐strand breaks in yeast and human cells. Lipid droplets accumulate in response to DNA double‐strand breaks DNA break‐induced sterol storage into lipid droplets lowers their level at the endoplasmic reticulum (ER) Low ER sterol levels decrease OSBP1 activity, which stabilizes PI(4)P at the Golgi Golgi‐stabilized PI(4)P binds the DDR kinase Tel1/ATM, titrating it from the nucleus Graphical Abstract Phosphatidylinositol‐4‐phosphate binding at the Golgi alters Tel1/ATM master kinase availability in the nucleus, thereby impacting the kinetics, intensity, and persistence of the response to DNA double‐strand breaks.