APC/C-CDH1 suppresses AROS-mediated protection against DNA damage-induced senescence by ubiquitination.

Abstract

Anaphase-promoting complex/cyclosome (APC/C) regulates the cell cycle by destruction of target proteins ubiquitination. However, understanding the control of APC/C has remained elusive. We identify APC2, the catalytic core subunit of APC/C, as a binding partner of active regulator of SIRT1 (AROS). Subsequent immunoprecipitation assays confirm the interaction in vivo. We reveal that AROS competes with APC11 for APC2 binding, thereby impeding the destruction of Cyclin B1. By contrast, the APC/C coactivator CDH1 ubiquitinates and degrades AROS in a D-box-dependent manner. Finally, we demonstrate that CDH1 suppresses the AROS-mediated protection of DNA damage-induced senescence. Overall, our findings provide evidence of the reciprocal role of AROS and APC/C-CDH1 in regulating APC/C activity and DNA damage-induced senescence, and highlight a potential role for AROS in the control of senescence.