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Related Experiment Videos

Coding sequence-dependent ribosomal arrest at termination of translation

J Cao1, A P Geballe

  • 1Division of Molecular Medicine and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.

Molecular and Cellular Biology
|February 1, 1996
PubMed
Summary

Short upstream open reading frames (uORFs) regulate gene expression. In human cytomegalovirus, a specific uORF (uORF2) peptide causes ribosomal stalling at its termination codon, inhibiting downstream protein production.

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Area of Science:

  • Molecular Biology
  • Virology
  • Gene Regulation

Background:

  • Short upstream open reading frames (uORFs) are common in viral and cellular transcripts but their regulatory roles are not fully understood.
  • The human cytomegalovirus gpUL4 (gp48) transcript features three uORFs, with uORF2 known to inhibit downstream translation.

Purpose of the Study:

  • To investigate the mechanism by which uORF2 inhibits translation of the downstream cistron.
  • To determine if ribosomal stalling at uORF2 is responsible for translational inhibition.

Main Methods:

  • Adaptation of the toeprinting assay (ribosomal stalling detection) for use with the gp48 transcript.
  • Utilizing a cell-free translation system to analyze ribosomal behavior on the mRNA.
  • In vivo validation of ribosomal stalling on the natural viral mRNA.

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Main Results:

  • Ribosomes were observed to stall at the termination codon of uORF2 in a cell-free system.
  • This stalling was dependent on the amino acid coding sequence of uORF2.
  • The sequence requirements for stalling matched those for downstream translation inhibition.
  • Evidence of ribosomal stalling at uORF2 was also found in vivo.

Conclusions:

  • uORF2 peptide-dependent ribosomal arrest at termination is the mechanism inhibiting downstream translation.
  • Translation termination can serve as a regulatory step in eukaryotic gene expression.
  • This finding provides insight into the complex regulation of viral gene expression.