CBFβ Regulates RUNX3 ADP-Ribosylation to Mediate Homologous Recombination Repair

RUNX3 is a master developmental transcriptional factor that has been implicated as a tumor suppressor in many cancers. However, the exact role of RUNX3 in cancer pathogenesis remains to be completely elucidated. Recently, it has emerged that RUNX3 is involved in the DNA damage response. Here, we demonstrate that heterodimerization of RUNX3 with CBFβ is necessary for its stability by protecting RUNX3 from RUNX3 ADP-ribosylation-dependent ubiquitination and degradation. We further identify new amino acid residues that are targets for PARylation and demonstrate that RUNX3 PARylation at these residues is necessary for localization of RUNX3 to DNA double strand break sites (DBSs). We also demonstrate that both RUNX3 PARylation and CBFβ heterodimerization with RUNX3 positively regulates homologous recombination (HR) repair, in part by promoting the recruitment of CtIP and phospho-RPA2 to the DBSs to mediate HR repair. In summary, we provide evidence that RUNX3 regulates HR repair activity in a PARylation-dependent manner.