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Published on: September 8, 2012

SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan

Eric Huntzinger1, Isao Kashima, Maria Fauser

  • 1Max Planck Institute for Developmental Biology, D-72076 Tübingen, Germany.

RNA (New York, N.Y.)
|November 1, 2008
PubMed

Insights

SMG6 is identified as the endonuclease that initiates nonsense-mediated mRNA decay (NMD) by cleaving messenger RNAs with premature translation termination codons (PTCs). This discovery reveals SMG6

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Nonsense-mediated mRNA decay (NMD) is a crucial cellular quality control pathway.
  • NMD prevents the synthesis of potentially harmful truncated proteins by degrading aberrant mRNAs.
  • The specific endonuclease responsible for initiating NMD-mediated mRNA cleavage remained unidentified.

Purpose of the Study:

  • To identify the endonuclease enzyme that initiates the degradation of PTC-containing mRNAs in Drosophila melanogaster.
  • To elucidate the enzymatic function and conservation of the identified endonuclease in metazoan NMD.

Main Methods:

  • Utilized genetic approaches in Drosophila melanogaster to assess the role of SMG6 in mRNA decay.
  • Performed site-directed mutagenesis to investigate the catalytic activity of SMG6.
  • Investigated the functional conservation of SMG6 endonuclease activity in human cells.

Main Results:

  • Cells expressing catalytically inactive SMG6 mutants failed to degrade PTC-containing mRNAs.
  • The endonuclease activity of SMG6, provided by its PIN domain, is essential for NMD.
  • SMG6's catalytic activity was found to be essential for PTC-containing mRNA degradation in human cells.

Conclusions:

  • SMG6 is the conserved endonuclease responsible for initiating nonsense-mediated mRNA decay in metazoa.
  • SMG6's catalytic activity is critical for degrading mRNAs with premature translation termination codons.
  • This finding clarifies a key step in a fundamental mRNA quality control pathway.

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