Selective Destabilization of Short-Lived mRNAs with the Granulocyte-Macrophage Colony-Stimulating Factor AU-Rich 3' Noncoding Region Is Mediated by a Cotranslational Mechanism

Abstract

The 3' noncoding region element (AUUUA)n specifically targets many short-lived mRNAs for degradation. Although the mechanism by which this sequence functions is not yet understood, a potential link between facilitated mRNA turnover and translation has been implied by the stabilization of cellular mRNAs in the presence of protein synthesis inhibitors. We therefore directly investigated the role of translation on mRNA stability. We demonstrate that mRNAs which are poorly translated through the introduction of stable secondary structure in the 5' noncoding region are not efficiently targeted for selective destabilization by the (AUUUA)n element. These results suggest that AUUUA-mediated degradation involves either a 5'-->3' exonuclease or is coupled to ongoing translation of the mRNA. To distinguish between these two possibilities, we inserted the poliovirus internal ribosome entry site, which promotes internal ribosome initiation, downstream of the 5' secondary structure. Translation directed by internal ribosome binding was found to fully restore targeted destabilization of AUUUA-containing mRNAs despite the presence of 5' secondary structure. This study therefore demonstrates that selective degradation mediated by the (AUUUA)n element is coupled to ribosome binding or ongoing translation of the mRNA and does not involve 5'-to-3' exonuclease activity.

Identifying the right stop: determining how the surveillance complex recognizes and degrades an aberrant mRNA

“…The half‐life of the histone transcript is not regulated in response to changes in DNA synthesis when the stability determinant is located at a distance >300 nt from the stop codon (Graves et al ., 1987). In addition, several studies indicate that the activity of the AU‐rich instability elements located in the 3′‐UTR of many unstable transcripts requires translation of the preceding coding region (Savant‐Bhonsale and Cleveland, 1992; Aharon and Schneider, 1993; Winstall et al ., 1995). For example, insertion of a strong stem‐loop structure between the termination codon and the AU‐rich element responsible for promoting decay of the granulocyte‐macrophage colony‐stimulating factor transcript prevented the rapid decay of this mRNA (Curatola et al ., 1995).…”

Participation of the human p53 3′UTR in translational repression and activation following γ-irradiation

“…Actively translated mRNAs, through their association with ribosomes, may become susceptible to a ribosome‐associated degradation process and exhibit increased decay in comparison with non‐translated mRNAs (Adamou and Bag, 1992; Kyrpides et al ., 1995). Alternatively, the process of mRNA unfolding during translation might disrupt structural features that are required for mRNA stability and accelerate mRNA turnover (Aharon and Schneider, 1993; Weiss and Liebhaber, 1995). In this regard, we note that the level of p53 mRNA does not change in irradiated cells even though we present evidence consistent with translational activation.…”

3‘ Untranslated Region-Mediated Regulation of Luteinizing Hormone/Human Chorionic Gonadotropin Receptor Expression

“…In the case of an mRNA containing the hepatitis B virus S-antigen open reading frame plus a 3′ UTR of the AU-rich region of GM-CSF mRNA, AUUUA-mediated mRNA degradation proceeds only when the message is undergoing active translation (Aharon & Schneider, 1993). Alternately, the degradation of c-fos may not involve a corequisite for translation (Koeller et al, 1991).…”

“…The interaction of luteinizing hormone (LH) or its placental counterpart human chorionic gonadotropin (hCG) with its specific receptor leads to activation of adenylate cyclase, which stimulates a number of intracellular functions, including steroidogenesis (Menon & Gunaga, 1974; Clark et al, 1976; Dufau, 1988). The rat LH/hCG receptor gene spans 75−96 kb, contains 11 exons (Tsai-Morris et al, 1991; Koo et al, 1991), and is processed into multiple mRNAs in all target tissues (Wang et al, 1991).…”