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

Ji-Hye Yang1, Hanbyeul Choi1, Seung Baek Lee2

  • 1Department of Molecular Biology, Dankook University, Cheonan 31116, Korea.

BMB Reports
|September 8, 2025
PubMed

Insights

Active regulator of SIRT1 (AROS) binds APC2, inhibiting cell cycle regulator Cyclin B1 destruction. APC/C-CDH1 degrades AROS, suppressing DNA damage-induced senescence, revealing a reciprocal regulatory role.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Anaphase-promoting complex/cyclosome (APC/C) is a crucial regulator of the cell cycle, controlling protein degradation through ubiquitination.
  • Mechanisms governing APC/C activity and its precise regulation remain incompletely understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling APC/C activity.
  • To investigate the role of the active regulator of SIRT1 (AROS) in APC/C function and cellular senescence.

Main Methods:

  • Co-immunoprecipitation assays to confirm protein interactions in vivo.
  • Analysis of protein binding competition between AROS, APC11, and APC2.
  • Assessment of Cyclin B1 degradation.
  • Investigation of AROS ubiquitination and degradation by CDH1.
  • Evaluation of CDH1's effect on AROS-mediated protection against DNA damage-induced senescence.

Main Results:

  • AROS directly interacts with APC2, a catalytic subunit of the APC/C.
  • AROS binding to APC2 impedes the ubiquitination and subsequent destruction of Cyclin B1.
  • The APC/C coactivator CDH1 ubiquitinates and degrades AROS in a D-box-dependent manner.
  • CDH1 antagonizes the protective effect of AROS against DNA damage-induced senescence.

Conclusions:

  • AROS acts as a negative regulator of APC/C activity by competing for APC2 binding, thereby stabilizing Cyclin B1.
  • CDH1 reciprocally regulates AROS stability, linking APC/C activity to senescence control.
  • These findings reveal a novel regulatory axis involving AROS and APC/C-CDH1 in managing DNA damage-induced senescence.

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