Linking Metabolism with DNA Repair: Role of ATP-Citrate Lyase

Maintaining genomic integrity and sustaining bioenergetics are both fundamental biological functions of normal proliferating cells. Crosstalk between metabolic and DNA repair pathways are poorly understood. Histone acetylation is a key factor in enabling recognition of DNA damage and in recruitment of DNA repair proteins to facilitate repair in a coordinated fashion. Acetyl-CoA modulations, in a nutrient sensitive manner, can influence global histone acetylation in proliferating cells. Given the importance of acetylation in the DNA damage response, we investigated a role for the metabolic regulation of histone acetylation following DNA damage. Herein, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455, downstream of ATM and AKT, following DNA damage in a cell-cycle dependent manner. Functionally, ACLY promotes histone acetylation at double strand break sites (DSBs) to facilitate BRCA1 recruitment at the expense of 53BP1 to facilitate homologous recombination. ACLY catalytic activity, phosphorylation, and nuclear localization enhances BRCA1 focal accumulation at damage sites. Loss of ACLY promotes genomic instability and cell death following PARP inhibition. Coordinated spatial and temporal regulation of ACLY-dependent acetyl-CoA production mediates homologous recombination at the expense of non-homologous end-joining