Emerging Themes in Regulation of Global mRNA Turnover in cis - PubMed (original) (raw)

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Emerging Themes in Regulation of Global mRNA Turnover in cis

Chyi-Ying A Chen et al. Trends Biochem Sci. 2017 Jan.

Abstract

mRNA is the molecule that conveys genetic information from DNA to the translation apparatus. mRNAs in all organisms display a wide range of stability, and mechanisms have evolved to selectively and differentially regulate individual mRNA stability in response to intracellular and extracellular cues. In recent years, three seemingly distinct aspects of RNA biology-mRNA N6-methyladenosine (m6A) modification, alternative 3' end processing and polyadenylation (APA), and mRNA codon usage-have been linked to mRNA turnover, and all three aspects function to regulate global mRNA stability in cis. Here, we discuss the discovery and molecular dissection of these mechanisms in relation to how they impact the intrinsic decay rate of mRNA in eukaryotes, leading to transcriptome reprogramming.

Keywords: alternative polyadenylation; codon optimality; m6A; mRNA turnover; transcriptome reprogramming.

Copyright © 2016 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1

Models of how m6A modification might affect the stability of a transcript. A. When a transcript gets m6A modification (red lollypops), binding of reader proteins to m6A modified site(s), particularly near the translation termination codon, may promote deadenylation of the targeted mRNA and enhance its degradation. B. An example illustrating how an m6A switch could control local RNA secondary structure. The m6A modification of a base-paired adenylate leads to exposure of a single-stranded RNA motif, facilitating its binding by a cognate RNA-binding protein (RBP). Depending on the nature of the RBP, the mRNA can be either destabilized or stabilized. C. HuR binding to a U-rich region in the 3’UTR results in stabilization of the targeted mRNA. When this binding is impaired by adjacent m6A residues, the mRNA is no longer stabilized by HuR. Not depicted are m6A modifications at other regions of mRNA and their effects on translation dynamics. Orange Pac man: deadenylase complex.

Figure 1

Figure 1

Models of how m6A modification might affect the stability of a transcript. A. When a transcript gets m6A modification (red lollypops), binding of reader proteins to m6A modified site(s), particularly near the translation termination codon, may promote deadenylation of the targeted mRNA and enhance its degradation. B. An example illustrating how an m6A switch could control local RNA secondary structure. The m6A modification of a base-paired adenylate leads to exposure of a single-stranded RNA motif, facilitating its binding by a cognate RNA-binding protein (RBP). Depending on the nature of the RBP, the mRNA can be either destabilized or stabilized. C. HuR binding to a U-rich region in the 3’UTR results in stabilization of the targeted mRNA. When this binding is impaired by adjacent m6A residues, the mRNA is no longer stabilized by HuR. Not depicted are m6A modifications at other regions of mRNA and their effects on translation dynamics. Orange Pac man: deadenylase complex.

Figure 1

Figure 1

Models of how m6A modification might affect the stability of a transcript. A. When a transcript gets m6A modification (red lollypops), binding of reader proteins to m6A modified site(s), particularly near the translation termination codon, may promote deadenylation of the targeted mRNA and enhance its degradation. B. An example illustrating how an m6A switch could control local RNA secondary structure. The m6A modification of a base-paired adenylate leads to exposure of a single-stranded RNA motif, facilitating its binding by a cognate RNA-binding protein (RBP). Depending on the nature of the RBP, the mRNA can be either destabilized or stabilized. C. HuR binding to a U-rich region in the 3’UTR results in stabilization of the targeted mRNA. When this binding is impaired by adjacent m6A residues, the mRNA is no longer stabilized by HuR. Not depicted are m6A modifications at other regions of mRNA and their effects on translation dynamics. Orange Pac man: deadenylase complex.

Figure 2

Figure 2

Models of how the choice between a proximal poly(A) site (pPAS) and a distal poly(A) site (dPAS) might affect mRNA stability. A. 3’UTR-APA eliciting loss of the negative regulatory elements leads to mRNA stabilization. Depicted in the 3’UTR are a microRNA binding site (miR-site), an AU-rich element (ARE), and a GU-rich element (GRE), each frequently found in unstable transcripts. B. When 3’UTR-APA elicits loss of positive regulatory elements, the mRNA is less stable. Depicted in the 3’UTR are two RNA stabilizing elements assumed to block deadenylase complex access to the poly(A) tail. Orange Pac man: deadenylase complex.

Figure 2

Figure 2

Models of how the choice between a proximal poly(A) site (pPAS) and a distal poly(A) site (dPAS) might affect mRNA stability. A. 3’UTR-APA eliciting loss of the negative regulatory elements leads to mRNA stabilization. Depicted in the 3’UTR are a microRNA binding site (miR-site), an AU-rich element (ARE), and a GU-rich element (GRE), each frequently found in unstable transcripts. B. When 3’UTR-APA elicits loss of positive regulatory elements, the mRNA is less stable. Depicted in the 3’UTR are two RNA stabilizing elements assumed to block deadenylase complex access to the poly(A) tail. Orange Pac man: deadenylase complex.

Figure 3

Figure 3

Model of two mRNAs with high and low codon optimality, respectively, differ in the traversing rate of their associated ribosomes. Note that ribosome loading or density may not be different between the two transcripts. Ribosomes traverse the ORF faster in the transcript with higher codon optimality (purple). Low codon optimality (light purple) triggers rapid deadenylation, followed by decapping and 5’ to 3’ digestion of RNA body (not depicted). The mechanism that senses the elongation rate and conveys it to the decay machinery is currently unknown. Pac man: deadenylase complex.

Figure 4

Figure 4

Key Figure: Three _cis_-acting molecular processes that may influence the intrinsic stability of eukaryotic mRNA under cellular conditions. While m6A modification (I) and APA (II) occur post-transcriptionally in the nucleus, the optimal codon content (III) of an ORF is encoded by the gene. The use of a proximal poly(A) site results in mRNA with a short 3’UTR (constitutive UTR or cUTR) by shortening of the longer 3’UTR (alternative UTR or aUTR). Thus, UTR-APA events are often accompanied by loss of RNA regulatory elements present in the aUTR. For the effect of codon optimality on mRNA stability to be triggered, a transcript must let ribosomes traverse the ORF. The summation of the final extent of m6A modification, the choice between a proximal poly(A) site (pPAS) and a distal poly(A) site (dPAS), and the optimal codon content of a transcript helps set its intrinsic decay rate in the cytoplasm.

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