Transcriptional Silencing of Nonsense Codon-Containing Immunoglobulin Minigenes

Cells possess mechanisms to prevent synthesis of potentially deleterious truncated proteins caused by premature translation-termination codons (PTCs). Here, we show that PTCs can induce silencing of transcription of its cognate gene. We demonstrate for immunoglobulin (Ig)-μ minigenes expressed in He...

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Bibliographic Details
Published in:Molecular cell 2005-04, Vol.18 (3), p.307-317
Main Authors: Bühler, Marc, Mohn, Fabio, Stalder, Lukas, Mühlemann, Oliver
Format: Article
Language:English
Subjects:
Base Sequence
Codon, Nonsense
Exonucleases - metabolism
Gene Silencing
Genes, Immunoglobulin
Genes, Reporter
HeLa Cells
Histone Deacetylase Inhibitors
Histone Deacetylases - metabolism
Histones - metabolism
Humans
Immunoglobulins - genetics
Lysine - metabolism
Methylation
RNA Interference
Sequence Alignment
Transcription, Genetic
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Summary:Cells possess mechanisms to prevent synthesis of potentially deleterious truncated proteins caused by premature translation-termination codons (PTCs). Here, we show that PTCs can induce silencing of transcription of its cognate gene. We demonstrate for immunoglobulin (Ig)-μ minigenes expressed in HeLa cells that this transcriptional silencing is PTC specific and reversible by treatment of the cells with histone deacetylase inhibitors. Furthermore, PTC-containing Ig-μ minigenes are significantly more associated with K9-methylated histone H3 and less associated with acetylated H3 than the PTC-free Ig-μ minigene. This nonsense-mediated transcriptional gene silencing (NMTGS) is also observed with an Ig-γ minigene, but not with several classic NMD reporter genes, suggesting that NMTGS might be specific for Ig genes. NMTGS represents a nonsense surveillance mechanism by which truncation of a gene’s open reading frame (ORF) induces transcriptional silencing through chromatin remodeling. Remarkably, NMTGS is inhibited by overexpression of the putative siRNase 3′hExo, suggesting that siRNA-like molecules are involved in NMTGS.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2005.03.030