GSK3β and Plk1 sequentially phosphorylate ATP–citrate lyase to promote homologous recombination
2026-09-09
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 Ser 455 , GSK3β phosphorylates ACLY at Thr 447 , generating a docking site for Plk1, which in turn phosphorylates ACLY at Ser 442 . 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.