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SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo

John H Kim1, Matthew S Modena1, Enisha Sehgal1

  • 1Department of MCD Biology, UC Santa Cruz, California, USA.

Nucleic Acids Research
|August 11, 2022
PubMed

Insights

Nonsense-mediated mRNA decay (NMD) prevents toxic truncated proteins. Researchers found SMG-6 endonuclease cleaves mRNA, causing ribosomes to stall and initiating NMD, a key process in multicellular organisms.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Nonsense-mediated mRNA decay (NMD) is a crucial cellular surveillance pathway.
  • NMD eliminates aberrant mRNAs containing premature termination codons (PTCs).
  • This prevents the accumulation of potentially toxic truncated proteins.

Purpose of the Study:

  • To investigate the mechanism of NMD initiation.
  • To identify the molecular players involved in early NMD events.
  • To elucidate the role of the endonuclease SMG-6 in NMD.

Main Methods:

  • Genetic analysis in Caenorhabditis elegans.
  • Biochemical assays to study mRNA cleavage and ribosome stalling.
  • Comparative analysis in human cell lines.

Main Results:

  • Identified SMG-6 as the endonuclease responsible for cleaving mRNAs targeted by NMD.
  • Demonstrated that SMG-6 cleavage precedes ribosome stalling on the cleaved stop codon.
  • Established that this SMG-6-mediated cleavage is a key event in NMD initiation.
  • Confirmed the conserved role of SMG-6 in NMD across metazoans.

Conclusions:

  • NMD is initiated by SMG-6-mediated mRNA cleavage, leading to ribosome stalling.
  • This finding refines the existing model of NMD, placing SMG-6 activity upstream of ribosome release.
  • SMG-6 plays a central and conserved role in NMD in multicellular organisms.

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