ATGL-catalyzed lipid catabolism promotes DNA repair

Abstract

An imbalance of DNA damage over DNA repair contributes to the genomic instability that drives aging and numerous age-related diseases. While numerous DNA repair mechanisms have been elucidated over decades of study, little is known about the contribution of metabolism to genomic stability. We report that adipose triglyceride lipase (ATGL), a primary lipolytic enzyme, promotes DNA repair. We show that lipid droplets (LDs) accumulate in response to DNA damage and that inhibition of LD biogenesis before genotoxic stress increases the persistence of DNA damage. Overexpression of ATGL (increasing lipolysis) enhances DNA repair in response to etoposide and ionizing radiation, thus reducing DNA damage burden. Mechanistically, ATGL promotes bulk acetylation of chromatin-bound proteins and blockade of the histone acetyltransferase p300 negates these effects. Further, ATGL-induced DNA repair attenuates the long-term consequences of DNA damage, and reducing senescence and enhancing viability. Overall, these studies reveal a novel role for LDs and LD proteins in DNA damage and repair, thus unveiling a mechanism through which lipid metabolism contributes to genomic stability.