Transcriptional silencing of nonsense codon-containing immunoglobulin minigenes

Abstract

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)-mu 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-mu minigenes are significantly more associated with K9-methylated histone H3 and less associated with acetylated H3 than the PTC-free Ig-mu minigene. This nonsense-mediated transcriptional gene silencing (NMTGS) is also observed with an Ig-gamma 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.