Regulation of SIRT1 activity by genotoxic stress

Abstract

SIRT1 regulates a variety of cellular functions, including cellular stress responses and energy metabolism. SIRT1 activity is negatively regulated by DBC1 (Deleted in Breast Cancer 1) through direct binding. However, how the DBC1–SIRT1 interaction is regulated remains unclear. We found that the DBC1–SIRT1 interaction increases following DNA damage and oxidative stress. The stress-induced DBC1–SIRT1 interaction requires the ATM-dependent phosphorylation of DBC1 at Thr 454, which creates a second binding site for SIRT1. Finally, we showed that the stress-induced DBC1–SIRT1 interaction is important for cell fate determination following genotoxic stress. These results revealed a novel mechanism of SIRT1 regulation during genotoxic stress.