GSK3β and Plk1 sequentially phosphorylate ATP-citrate lyase to promote homologous recombination.

Abstract

Accurate repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is essential for genome stability. Nuclear production of acetyl-coenzyme A (acetyl-CoA) by ATP-citrate lyase (ACLY) promotes HR, yet how ACLY is regulated during the DNA damage response (DDR) remains unclear. Here, we identify a phosphorylation-dependent signaling axis in which glycogen synthase kinase 3β (GSK3β) and Polo-like kinase 1 (Plk1) act sequentially on ACLY to facilitate HR-mediated repair of DSBs induced by ionizing radiation. Following AKT-dependent phosphorylation of ACLY at Ser455, GSK3β phosphorylates ACLY at Thr447, generating a docking site for Plk1, which in turn phosphorylates ACLY at Ser442. This phosphorylation cascade, enhanced by radiation, sustains histone acetylation, supports the accumulation of BRCA1 and RAD51 at DSBs, and confers cellular resistance to poly(ADP-ribose) polymerase (PARP) inhibition. Together, our findings define an AKT-GSK3β-Plk1-ACLY signaling module that links the DDR to nuclear metabolism, revealing a critical mechanism by which kinase signaling facilitates acetyl-CoA-dependent chromatin remodeling to preserve genome integrity.