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Chk1 and 14-3-3 proteins inhibit atypical E2Fs to prevent a permanent cell cycle arrest

Ruixue Yuan1, Harmjan R Vos2, Robert M van Es2

  • 1Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.

The EMBO Journal
|January 25, 2018
PubMed

Insights

Checkpoint kinase 1 (Chk1) and 14-3-3 proteins inactivate atypical E2Fs, crucial for suppressing tumors. This mechanism may be vital for cancer cells facing DNA-damaging therapies.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Cancer Biology

Background:

  • Atypical E2Fs (E2F7, E2F8) normally repress DNA replication genes, inducing S-phase arrest and suppressing tumors.
  • Elevated atypical E2F levels in human cancers suggest inhibited tumor suppressor functions via unknown post-translational modifications.

Purpose of the Study:

  • To investigate the post-translational mechanisms regulating atypical E2F function in cancer.
  • To identify how checkpoint kinase 1 (Chk1) and 14-3-3 proteins influence atypical E2Fs.

Main Methods:

  • Phosphorylation assays to determine Chk1's effect on E2F7/8.
  • Co-immunoprecipitation to assess 14-3-3 protein interactions with E2Fs.
  • Chromatin immunoprecipitation to analyze protein binding at target gene promoters.
  • Correlation analysis of 14-3-3 protein levels and target gene expression in human cancers.

Main Results:

  • Chk1 directly phosphorylates atypical E2Fs, preventing permanent S-phase arrest.
  • 14-3-3 proteins bind to E2Fs in a Chk1-dependent manner.
  • Chk1-mediated phosphorylation and 14-3-3 binding recruit 14-3-3 to E2F7/8 target gene promoters, interfering with transcription.
  • High 14-3-3 levels correlate with increased transcription of atypical E2F target genes in human cancers.

Conclusions:

  • Chk1 and 14-3-3 proteins cooperate to inactivate the transcriptional repressor activity of atypical E2Fs.
  • This inactivation mechanism is important for cancer cells, particularly under DNA-damaging therapeutic conditions.
  • Understanding this pathway offers potential therapeutic targets for cancer treatment.
Keywords:
14‐3‐3 proteinsDNA damageatypical E2Fscell cyclecheckpoint kinase 1

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