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DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity

Hedda A Meijer1, Tobias Schmidt1, Sarah L Gillen1

  • 1Medical Research Council (MRC), Toxicology Unit, University of Cambridge, Hodgkin Building, Leicester LE1 9HN, UK.

Nucleic Acids Research
|June 11, 2019
PubMed

Insights

The CCR4-NOT complex regulates mRNA fate. Specific helicases, eIF4A2 and DDX6, bind to CNOT1, influencing deadenylation and translation differently, thus controlling mRNA stability.

Area of Science:

  • Molecular Biology
  • RNA Biology
  • Gene Regulation

Background:

  • The CCR4-NOT complex is a key regulator of mRNA translational repression and deadenylation.
  • The specific roles of factors interacting with the CCR4-NOT complex remain largely uncharacterized.

Purpose of the Study:

  • To investigate the distinct roles of DEAD-box helicases eIF4A2 and DDX6 in modulating CCR4-NOT complex activity.
  • To understand how these helicases affect mRNA deadenylation and translational control.

Main Methods:

  • Protein-protein interaction assays to study binding of eIF4A2 and DDX6 to CNOT1.
  • Enzymatic assays to measure CNOT7 deadenylation activity in the presence of helicases.
  • Polyadenylation tests (PAT) on endogenous mRNAs.
  • Immunoprecipitation experiments to assess complex formation and activity.

Main Results:

  • eIF4A2 and DDX6 directly bind to CNOT1 and compete for binding.
  • eIF4A2 inhibits CNOT7 deadenylation activity, while DDX6 enhances it.
  • eIF4A2-bound mRNAs exhibit longer poly(A) tails compared to DDX6-bound mRNAs.
  • TAB182 was identified as a factor modulating helicase recruitment to the CCR4-NOT complex.

Conclusions:

  • The recruitment of either eIF4A2 or DDX6 to the CCR4-NOT complex dictates distinct pathways for translational repression and mRNA deadenylation.
  • mRNA fate is determined by the specific helicase engaged with the CCR4-NOT complex.
  • These findings elucidate a novel mechanism of post-transcriptional gene regulation.

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