Modification of DBC1 by SUMO2/3 is crucial for p53-mediated apoptosis in response to DNA damage

DBC1 is a major inhibitor of SIRT1, which plays critical roles in the control of diverse cellular processes, including stress response and energy metabolism. Therefore, the DBC1–SIRT1 interaction should finely be regulated. Here we report that DBC1 modification by Small Ubiquitin-like Modifier 2/3 (SUMO 2/3), but not by SUMO1, is crucial for p53 transactivation under genotoxic stress. Whereas etoposide treatment reduced the interaction of DBC1 with SENP1, it promoted that with PIAS3, resulting in an increase in DBC1 sumoylation. Remarkably, the switching from SENP1 to PIAS3 for DBC1 binding was achieved by ATM/ATR-mediated phosphorylation of DBC1. Furthermore, DBC1 sumoylation caused an increase in the DBC1–SIRT1 interaction, leading to the release of p53 from SIRT1 for transcriptional activation. Consistently, SENP1 knockdown promoted etoposide-induced apoptosis, whereas knockdown of PIAS3 or SUMO2/3 and overexpression of sumoylation-deficient DBC1 mutant inhibited it. These results establish the role of DBC1 sumoylation in the promotion of p53-mediated apoptosis in response to genotoxic stress. SIRT1 is a deacetylase that is negatively regulated by binding to DBC1. Here Park et al. show that DNA damage-induced SUMO2/3 conjugation of DBC1 promotes the SIRT1–DBC1 interaction, leading to an increase in acetylated p53 and induction of apoptosis.