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Transcriptional silencing of nonsense codon-containing immunoglobulin micro genes requires translation of its mRNA

Lukas Stalder1, Oliver Mühlemann

  • 1Institute of Cell Biology, University of Berne, Baltzerstrasse 4, CH-3012 Bern, Switzerland.

The Journal of Biological Chemistry
|April 13, 2007
PubMed

Insights

Eukaryotic cells prevent faulty gene expression using quality control. Premature translation-termination codon (PTC) containing genes trigger nonsense-mediated transcriptional gene silencing (NMTGS) and mRNA decay (NMD) via a linked pathway.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Eukaryotes possess quality control mechanisms to prevent expression of genes with premature translation-termination codons (PTCs).
  • Nonsense-mediated mRNA decay (NMD) is a known posttranscriptional mechanism targeting PTC-containing mRNAs.
  • Previous work identified transcriptional silencing of PTC-containing immunoglobulin (Ig) minigenes.

Purpose of the Study:

  • To investigate the mechanism of transcriptional silencing of PTC-containing immunoglobulin (Ig) minigenes.
  • To determine the relationship between nonsense-mediated transcriptional gene silencing (NMTGS) and NMD.

Main Methods:

  • Utilized stably integrated PTC-containing Ig-mu minigenes in HeLa cells.
  • Manipulated mRNA translation using an iron-responsive element in the 5'-untranslated region.
  • Employed RNA interference (RNAi) to deplete the NMD factor Upf1.

Main Results:

  • Transcriptional silencing of PTC-containing Ig-mu constructs requires active mRNA translation.
  • Inhibition of translation prevented NMTGS.
  • Depletion of Upf1 abolished NMD and reduced NMTGS, indicating a link between the pathways.

Conclusions:

  • Nonsense-mediated transcriptional gene silencing (NMTGS) and NMD are interconnected processes.
  • Both pathways utilize a common mechanism for premature translation-termination codon (PTC) recognition.
  • NMTGS branches from the NMD pathway downstream of Upf1 function.

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