| Abstract |
DNA double-strand breaks (DSBs) represent a major threat to genomic integrity. DSBs are primarily repaired through homologous recombination (HR) and non-homologous end-joining (NHEJ). The Ku complex, composed of XRCC5 and XRCC6, initiates NHEJ by binding to the DNA ends in DSBs. Our previous study demonstrated that FOXL2 regulates Ku availability through acetylation-dependent interaction; however, whether related mechanisms operate across other FOX family proteins and how these can be regulated in response to genotoxic stress remain unclear.In this study, we demonstrated that multiple FOX family members interact with XRCC5/6 and acetylation-dependently suppress NHEJ. GCN5 (KAT2A) promoted the acetylation of a conserved lysine residue within the forkhead domain, thereby enhancing FOX-Ku association and limiting Ku availability. In response to DNA damage, SIRT1 underwent SUMOylation at lysine 734, thereby promoting its nuclear accumulation through KPNA2/KPNA3-dependent import. Nuclear SIRT1 acted as a deacetylase and reversed FOX acetylation, thereby reducing FOX-Ku interaction and permitting NHEJ activation.The results of this study define a DNA damage-responsive GCN5-SIRT1 regulatory axis that modulates FOX acetylation, FOX-Ku interaction, and NHEJ activity. Our study extends FOXL2-centered findings and supports a shared, but context-dependent, DNA repair regulation-supporting mechanism involving multiple FOX proteins.
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