Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination

5 years ago

Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination

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

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Sivanand et al. demonstrate that ACLY is phosphorylated at S455 within the nucleus following DNA damage in a cell-cycle-dependent manner. ACLY promotes histone acetylation near double-strand breaks and facilitates BRCA1 recruitment and homologous recombination. ACLY phosphorylation and nuclear localization are required for its role in regulating BRCA1 recruitment.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517304355