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Phosphorylation-triggered CUEDC2 degradation promotes UV-induced G1 arrest through APC/C(Cdh1) regulation

Wei-Na Zhang1, Jie Zhou, Tao Zhou

  • 1Beijing Institute of Biotechnology, Beijing 100071, China.

Proceedings of the National Academy of Sciences of the United States of America
|June 19, 2013
PubMed

Insights

UV radiation triggers cell cycle arrest by degrading CUEDC2, a protein that inhibits APC/C(Cdh1). This degradation is crucial for blocking the G1-S transition and preventing genomic instability.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • DNA damage necessitates cell cycle arrest for repair, preventing genomic instability and cancer.
  • While p21 mediates G1 arrest in response to some DNA damage, its degradation limits its role in UV-induced G1 arrest, leaving the mechanism unclear.

Purpose of the Study:

  • To elucidate the mechanism of G1 arrest following UV irradiation.
  • To identify key regulators involved in UV-induced G1 arrest.

Main Methods:

  • Investigated the role of CUE domain-containing protein 2 (CUEDC2) in UV-induced G1 arrest.
  • Utilized biochemical assays to assess CUEDC2 binding to and inhibition of anaphase-promoting complex/cyclosome-Cdh1 (APC/C(Cdh1)).
  • Employed phosphorylation and degradation studies, including the use of a nonphosphorylatable CUEDC2 mutant, to analyze its regulation in response to UV.

Main Results:

  • CUEDC2 inhibits APC/C(Cdh1), stabilizing Cyclin A and promoting G1-S transition.
  • UV irradiation induces ERK1/2-dependent phosphorylation and degradation of CUEDC2.
  • CUEDC2 degradation leads to Cyclin A destruction, Cyclin-dependent kinase 2 inactivation, and subsequent G1 arrest.
  • A stable, nonphosphorylatable CUEDC2 mutant abrogates UV-induced G1-S block.

Conclusions:

  • CUEDC2 acts as a critical inhibitor of APC/C(Cdh1) in the G1 phase.
  • Regulated degradation of CUEDC2 is essential for initiating G1 arrest after UV exposure.
  • This pathway highlights a novel mechanism controlling cell cycle progression in response to UV damage.

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