The Role Of ATGL-Mediated Lipolysis In DNA Damage And Repair

Abstract

An imbalance of DNA damage over repair contributes to the genomic instability that drives aging and countless aging-related diseases. Fasting and caloric restriction are arguably the most well-established interventions that extend lifespan across organisms, a mechanism supported by evidence that fasting can enhance genomic stability. In a fasting state, the upregulation of lipolytic enzymes such as adipose triglyceride lipase (ATGL) leads to the breakdown of lipid droplets (LDs), a process known to impact metabolism and cell signaling. Given the contributory role of LDs and ATGL in the fasting response and the link between fasting and genomic stability, our objective is to elucidate the mechanisms by which LD metabolism regulates genomic stability. We show in multiple cell types that LDs accumulate in response to DNA damage and that ablation of LDs (via inhibition of LD biogenesis) before genotoxic stress increases the persistence of DNA damage and increases senescence. Importantly, we show that overexpression of ATGL (increasing lipolysis) reduces DNA damage and enhances DNA repair in response to both etoposide and ionizing radiation. These findings are recapitulated in mice as genetic lines globally overexpressing ATGL are better able to resolve DNA damage after irradiation. Additional data indicate that pharmacological upregulation of lipolysis can enhance DNA repair, providing both proof of concept for the ATGL studies and an exciting potential intervention for populations undergoing large amounts of DNA damage (e.g., patients undergoing chemotherapy). Finally, our data suggest that ATGL promotes fatty acid oxidation and subsequent production of acetyl-CoA intermediates, which promote acetylation that facilitates DNA repair. Overall, these studies reveal a novel role for LDs and LD proteins in DNA damage and repair, thus unveiling a novel mechanism by which altered metabolism contributes to genomic stability and aging.