Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination

Summary While maintaining the integrity of the genome and sustaining bioenergeticsare both fundamental functions of the cell, potential crosstalk between metabolic and DNA repairpathways is poorly understood. Since histone acetylationplays important roles in DNA repairand is sensitive to the availability of acetylcoenzyme A ( acetyl-CoA), we investigated a role for metabolic regulation of histone acetylationduring the DNA damage response. In this study, we report that nuclear ATP-citrate lyase(ACLY) is phosphorylated at S455 downstream of ataxia telangiectasiamutated (ATM) and AKT following DNA damage. ACLY facilitates histone acetylationat double-strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repairby homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment. Upon PARP inhibition, ACLY silencing promotes genomic instabilityand cell death. Thus, the spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repairpathway choice.