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A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

Nana Zheng1, Xiangpeng Dai2, Zhiwei Wang1

  • 1a The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University , Suzhou , P. R. China.

Cell Cycle (Georgetown, Tex.)
|September 22, 2016
PubMed

Insights

The study reveals that the SCFβ-TRCP E3 ligase complex targets the Set8 protein for degradation via CKI-mediated phosphorylation. This mechanism is crucial for controlling cell proliferation and cell cycle progression after UV irradiation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Set8 is essential for transcription regulation, cell cycle progression, and genomic stability.
  • Previous studies identified CRL4cdt2 and SCFSkp2 E3 ligases regulating Set8 protein levels.
  • The role of other E3 ligases in controlling Set8 during genotoxic stress remained unclear.

Purpose of the Study:

  • To investigate the role of other E3 ligases in regulating Set8 protein stability in response to genotoxic stress.
  • To elucidate the mechanism by which SCFβ-TRCP influences Set8 protein levels.
  • To understand the contribution of SCFβ-TRCP-mediated Set8 degradation to cell cycle control following UV irradiation.

Main Methods:

  • Co-immunoprecipitation assays to detect Set8 and SCFβ-TRCP interaction.
  • Western blotting to assess Set8 protein levels and ubiquitination.
  • Site-directed mutagenesis to investigate the role of Set8 phosphorylation at S253.
  • Cell cycle analysis and proliferation assays in response to UV irradiation.

Main Results:

  • Set8 directly interacts with the SCFβ-TRCP E3 ligase complex.
  • CKI-mediated phosphorylation of Set8 at the S253 site promotes its ubiquitination and degradation by SCFβ-TRCP.
  • SCFβ-TRCP-dependent degradation of Set8 is essential for proper cell proliferation and cell cycle progression after UV exposure.
  • Dysregulation of this regulatory network can lead to aberrant cell cycle processes.

Conclusions:

  • The SCFβ-TRCP E3 ligase complex, in conjunction with CKI, plays a critical role in regulating Set8 protein stability.
  • This regulatory pathway is vital for maintaining cell cycle control and genomic stability under genotoxic stress conditions like UV irradiation.
  • Understanding the β-TRCP/CKI/Set8 axis offers insights into potential therapeutic targets for cell cycle-related disorders.
Keywords:
Cell cycleDNA damageSet8Ubiquitincell proliferationβ-TRCP

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