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.

Automated summary

Upon DNA damage, cells activate the DNA damage response to coordinate proliferation and DNA repair. Lipids have the potential to convey signals that modulate DNA surveillance and repair, although the underlying mechanisms are poorly understood. In this study, we found that the number of lipid droplets specifically increased in response to DNA breaks. We demonstrated that the storage of sterols in these droplets stabilizes phosphatidylinositol-4-phosphate (PI(4)P) at the Golgi, which binds to the DDR kinase ATM and attenuates the initial nuclear ATM-driven response to DNA breaks. This finding has important implications for addressing genetic instability pathologies through dietary and pharmacological interventions.