When mRNA translation meets decay

2017 ◽  
Vol 45 (2) ◽  
pp. 339-351 ◽  
Author(s):  
Alicia A. Bicknell ◽  
Emiliano P. Ricci
Keyword(s):  
Mrna Stability ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Mrna Translation ◽  
Mrna Degradation ◽  
Mrna Surveillance ◽  
Protein Output

Messenger RNA (mRNA) translation and mRNA degradation are important determinants of protein output, and they are interconnected. Previously, it was thought that translation of an mRNA, as a rule, prevents its degradation. mRNA surveillance mechanisms, which degrade mRNAs as a consequence of their translation, were considered to be exceptions to this rule. Recently, however, it has become clear that many mRNAs are degraded co-translationally, and it has emerged that codon choice, by influencing the rate of ribosome elongation, affects the rate of mRNA decay. In this review, we discuss the links between translation and mRNA stability, with an emphasis on emerging data suggesting that codon optimality may regulate mRNA degradation.

scholarly journals The Ccr4-Not complex monitors the translating ribosome for codon optimality

Science ◽  
2020 ◽  
Vol 368 (6488) ◽  
pp. eaay6912 ◽  
Author(s):  
Robert Buschauer ◽  
Yoshitaka Matsuo ◽  
Takato Sugiyama ◽  
Ying-Hsin Chen ◽  
Najwa Alhusaini ◽  
...  
Keyword(s):  
Mrna Stability ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Specific Interaction ◽  
Ribosome Profiling ◽  
Translation Elongation ◽  
Cryo Electron Microscopy ◽  
A Site ◽  
Sense Codon ◽  
Decoding Efficiency

Control of messenger RNA (mRNA) decay rate is intimately connected to translation elongation, but the spatial coordination of these events is poorly understood. The Ccr4-Not complex initiates mRNA decay through deadenylation and activation of decapping. We used a combination of cryo–electron microscopy, ribosome profiling, and mRNA stability assays to examine the recruitment of Ccr4-Not to the ribosome via specific interaction of the Not5 subunit with the ribosomal E-site in Saccharomyces cerevisiae. This interaction occurred when the ribosome lacked accommodated A-site transfer RNA, indicative of low codon optimality. Loss of the interaction resulted in the inability of the mRNA degradation machinery to sense codon optimality. Our findings elucidate a physical link between the Ccr4-Not complex and the ribosome and provide mechanistic insight into the coupling of decoding efficiency with mRNA stability.

mRNA degradation and maturation in prokaryotes: the global players

2011 ◽  
Vol 2 (6) ◽  
pp. 491-506 ◽  
Author(s):  
Soumaya Laalami ◽  
Harald Putzer
Keyword(s):  
Protein Synthesis ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Mrna Degradation ◽  
Mrna Turnover ◽  
Model Organisms ◽  
Translation Regulation ◽  
Ecological Niches ◽  
Rnase E ◽  
General Role

AbstractThe degradation of messenger RNA is of universal importance for controlling gene expression. It directly affects protein synthesis by modulating the amount of mRNA available for translation. Regulation of mRNA decay provides an efficient means to produce just the proteins needed and to rapidly alter patterns of protein synthesis. In bacteria, the half-lives of individual mRNAs can differ by as much as two orders of magnitude, ranging from seconds to an hour. Most of what we know today about the diverse mechanisms of mRNA decay and maturation in prokaryotes comes from studies of the two model organisms Escherichia coli and Bacillus subtilis. Their evolutionary distance provided a large picture of potential pathways and enzymes involved in mRNA turnover. Among them are three ribonucleases, two of which have been discovered only recently, which have a truly general role in the initiating events of mRNA degradation: RNase E, RNase J and RNase Y. Their enzymatic characteristics probably determine the strategies of mRNA metabolism in the organism in which they are present. These ribonucleases are coded, alone or in various combinations, in all prokaryotic genomes, thus reflecting how mRNA turnover has been adapted to different ecological niches throughout evolution.

scholarly journals Cotranslational microRNA mediated messenger RNA destabilization

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Trinh To Tat ◽  
Patricia A Maroney ◽  
Sangpen Chamnongpol ◽  
Jeff Coller ◽  
Timothy W Nilsen
Keyword(s):  
Messenger Rna ◽  
Protein Production ◽  
Mrna Decay ◽  
Mrna Degradation ◽  
Free State ◽  
Biological Processes ◽  
Base Pairing ◽  
Considerable Evidence ◽  
Decay Model ◽  
Limited Base

MicroRNAs are small (22 nucleotide) regulatory molecules that play important roles in a wide variety of biological processes. These RNAs, which bind to targeted mRNAs via limited base pairing interactions, act to reduce protein production from those mRNAs. Considerable evidence indicates that miRNAs destabilize targeted mRNAs by recruiting enzymes that function in normal mRNA decay and mRNA degradation is widely thought to occur when mRNAs are in a ribosome free state. Nevertheless, when examined, miRNA targeted mRNAs are invariably found to be polysome associated; observations that appear to be at face value incompatible with a simple decay model. Here, we provide evidence that turnover of miRNA-targeted mRNAs occurs while they are being translated. Cotranslational mRNA degradation is initiated by decapping and proceeds 5’ to 3’ behind the last translating ribosome. These results provide an explanation for a long standing mystery in the miRNA field.

Functions of microRNAs in Drosophila development

2010 ◽  
Vol 38 (4) ◽  
pp. 1137-1143 ◽  
Author(s):  
Christopher I. Jones ◽  
Sarah F. Newbury
Keyword(s):  
Mrna Stability ◽  
Molecular Mechanisms ◽  
Mrna Translation ◽  
Mrna Degradation ◽  
Mrna Turnover ◽  
Factors Affecting ◽  
Biologically Relevant ◽  
The Core ◽  
Cellular Factors

Control of mRNA translation and degradation has been shown to be key in the development of complex organisms. The core mRNA degradation machinery is highly conserved in eukaryotes and relies on processive degradation enzymes gaining access to the mRNA. Control of mRNA stability in eukaryotes is also intimately linked to the regulation of translation. A key question in the control of mRNA turnover concerns the mechanisms whereby particular mRNAs are specifically degraded in response to cellular factors. Recently, microRNAs have been shown to bind specifically to mRNAs and regulate their expression via repression of translation and/or degradation. To understand the molecular mechanisms during microRNA repression of mRNAs, it is necessary to identify their biologically relevant targets. However, computational methods have so far proved unreliable, therefore verification of biologically important targets at present requires experimental analysis. The present review aims to outline the mechanisms of mRNA degradation and then focus on the role of microRNAs as factors affecting particular Drosophila developmental processes via their post-transcriptional effects on mRNA degradation and translation. Examples of experimentally verified targets of microRNAs in Drosophila are summarized.

scholarly journals Transient ribosome slowdown at the decoding step triggers mRNA degradation independent of Znf598 in zebrafish

2021 ◽  
Author(s):  
Yuichiro Mishima ◽  
Peixun Han ◽  
Seisuke Kimura ◽  
Shintaro Iwasaki
Keyword(s):  
Mrna Stability ◽  
Mrna Decay ◽  
Expression Patterns ◽  
Mrna Degradation ◽  
Zebrafish Embryos ◽  
Reading Frame ◽  
Genome Wide ◽  
Codon Composition ◽  
Kinetics Of

The control of mRNA stability plays a central role in regulating gene expression patterns. Recent studies have revealed that codon composition in the open reading frame (ORF) determines mRNA stability in multiple organisms. Based on genome-wide correlation approaches, this previously unrecognized role of the genetic code is attributable to the kinetics of the codon-decoding process by the ribosome. However, complementary experimental analysis is required to define the codon effects on mRNA stability apart from the related cotranslational mRNA decay pathways such as those triggered by aberrant ribosome stalls. In the current study, we performed a set of reporter-based analyses to define codon-mediated mRNA decay and ribosome stall-dependent mRNA decay in zebrafish embryos. Our analysis showed that the effect of codons on mRNA stability stems from the decoding process, independent of Znf598 and stall-dependent mRNA decay. We propose that codon-mediated mRNA decay is triggered by transiently slowed ribosomes engaging in a productive translation cycle in zebrafish embryos.

scholarly journals Dcp2 phosphorylation by Ste20 modulates stress granule assembly and mRNA decay in Saccharomyces cerevisiae

2010 ◽  
Vol 189 (5) ◽  
pp. 813-827 ◽  
Author(s):  
Je-Hyun Yoon ◽  
Eui-Ju Choi ◽  
Roy Parker
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Interactions ◽  
Messenger Rna ◽  
Mrna Decay ◽  
Control Point ◽  
Stress Granules ◽  
Mrna Degradation ◽  
Stress Granule ◽  
Granule Formation ◽  
P Bodies

Translation and messenger RNA (mRNA) degradation are important sites of gene regulation, particularly during stress where translation and mRNA degradation are reprogrammed to stabilize bulk mRNAs and to preferentially translate mRNAs required for the stress response. During stress, untranslating mRNAs accumulate both in processing bodies (P-bodies), which contain some translation repressors and the mRNA degradation machinery, and in stress granules, which contain mRNAs stalled in translation initiation. How signal transduction pathways impinge on proteins modulating P-body and stress granule formation and function is unknown. We show that during stress in Saccharomyces cerevisiae, Dcp2 is phosphorylated on serine 137 by the Ste20 kinase. Phosphorylation of Dcp2 affects the decay of some mRNAs and is required for Dcp2 accumulation in P-bodies and specific protein interactions of Dcp2 and for efficient formation of stress granules. These results demonstrate that Ste20 has an unexpected role in the modulation of mRNA decay and translation and that phosphorylation of Dcp2 is an important control point for mRNA decapping.

scholarly journals P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization

2018 ◽  
Vol 29 (8) ◽  
pp. 988-1002 ◽  
Author(s):  
Mei-Yan Qi ◽  
Jing-Wen Song ◽  
Zhuo Zhang ◽  
Shuang Huang ◽  
Qing Jing
Keyword(s):  
Mrna Stability ◽  
Mrna Decay ◽  
Mrna Degradation ◽  
Processing Bodies ◽  
Mrna Stabilization ◽  
Argonaute 2 ◽  
Core Member ◽  
Mrna Granules

Tristetraprolin (TTP) destabilizes AU-rich element (ARE)-containing mRNA by directly binding with their 3′UTR. P38 stimulation substantially increases ARE-mRNA stability, at least through repressing TTP. However, the mechanism by which P38 keeps TTP inactive has not been fully understood. TTP and ARE-mRNA localize to processing bodies (PBs), the mRNA granules associated with mRNA silencing. Here, we detected the influence of P38 on TTP localization within PBs and found that P38 regulates TTP localization within PBs. Through luciferase-based systems, we demonstrated that PBs depletion significantly increased ARE-mRNA stability inhibited by TTP. Additionally, we provided evidence that the microRNA-induced silencing complex (miRISC) core member Ago2 is required for TTP distribution within PBs. Importantly, the cooperation of TTP and Ago2 is a prerequisite for effective ARE-mRNA degradation. Moreover, Dcp1a and Dcp2 act downstream of Ago2 and TTP engaging in ARE-mRNA decay. Finally, we demonstrated that P38 activation represses the interaction between TTP and Ago2 due to TTP phosphorylation, which impairs TTP localization within PBs and ARE-mRNA degradation. Collectively, our study revealed a novel mechanism through which P38 activation repressed the cooperation of TTP with Ago2, thus ensuring that ARE-mRNA does not associate with PBs and remains stable.

scholarly journals Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1

2013 ◽  
Vol 202 (1) ◽  
pp. 53-69 ◽  
Author(s):  
Natasha M. Sosanya ◽  
Peggy P.C. Huang ◽  
Luisa P. Cacheaux ◽  
Chun Jung Chen ◽  
Kathleen Nguyen ◽  
...  
Keyword(s):  
Mrna Stability ◽  
Messenger Rna ◽  
Translational Regulation ◽  
Rna Binding ◽  
Mrna Translation ◽  
Intrinsic Excitability ◽  
Site Specific ◽  
Voltage Gated ◽  
High Affinity ◽  
Mtorc1 Signaling

Little is known about how a neuron undergoes site-specific changes in intrinsic excitability during neuronal activity. We provide evidence for a novel mechanism for mTORC1 kinase–dependent translational regulation of the voltage-gated potassium channel Kv1.1 messenger RNA (mRNA). We identified a microRNA, miR-129, that repressed Kv1.1 mRNA translation when mTORC1 was active. When mTORC1 was inactive, we found that the RNA-binding protein, HuD, bound to Kv1.1 mRNA and promoted its translation. Unexpectedly, inhibition of mTORC1 activity did not alter levels of miR-129 and HuD to favor binding to Kv1.1 mRNA. However, reduced mTORC1 signaling caused the degradation of high affinity HuD target mRNAs, freeing HuD to bind Kv1.1 mRNA. Hence, mTORC1 activity regulation of mRNA stability and high affinity HuD-target mRNA degradation mediates the bidirectional expression of dendritic Kv1.1 ion channels.

scholarly journals Scavenger Decapping Activity Facilitates 5′ to 3′ mRNA Decay

2005 ◽  
Vol 25 (22) ◽  
pp. 9764-9772 ◽  
Author(s):  
Hudan Liu ◽  
Megerditch Kiledjian
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mrna Stability ◽  
Mrna Decay ◽  
Hydrolytic Activity ◽  
Mrna Degradation ◽  
Mrna Turnover ◽  
Threefold Increase ◽  
Mechanistic Analysis ◽  
Decapping Enzyme ◽  
Mrna Half Life

ABSTRACT mRNA degradation occurs through distinct pathways, one primarily from the 5′ end of the mRNA and the second from the 3′ end. Decay from the 3′ end generates the m7GpppN cap dinucleotide, which is subsequently hydrolyzed to m7Gp and ppN in Saccharomyces cerevisiae by a scavenger decapping activity termed Dcs1p. Although Dcs1p functions in the last step of mRNA turnover, we demonstrate that its activity modulates earlier steps of mRNA decay. Disruption of the DCS1 gene manifests a threefold increase of the TIF51A mRNA half-life. Interestingly, the hydrolytic activity of Dcs1p was essential for the altered mRNA turnover, as Dcs1p, but not a catalytically inactive Dcs1p mutant, complemented the increased mRNA stability. Mechanistic analysis revealed that 5′ to 3′ exoribonucleolytic activity was impeded in the dcs1Δ strain, resulting in the accumulation of uncapped mRNA. These data define a new role for the Dcs1p scavenger decapping enzyme and demonstrate a novel mechanism whereby the final step in the 3′ mRNA decay pathway can influence 5′ to 3′ exoribonucleolytic activity.

scholarly journals Genetic compensation is triggered by mutant mRNA degradation

2018 ◽  
Author(s):  
Mohamed A. El-Brolosy ◽  
Andrea Rossi ◽  
Zacharias Kontarakis ◽  
Carsten Kuenne ◽  
Stefan Günther ◽  
...  
Keyword(s):  
Protein Function ◽  
Mrna Decay ◽  
Degradation Products ◽  
Sequence Similarity ◽  
Mrna Degradation ◽  
Mrna Surveillance ◽  
Transcriptional Modulation ◽  
Transcriptional Adaptation ◽  
Genetic Compensation

Genetic compensation by transcriptional modulation of related gene(s) (also known as transcriptional adaptation) has been reported in numerous systems1–3; however, whether and how such a response can be activated in the absence of protein feedback loops is unknown. Here, we develop and analyze several models of transcriptional adaptation in zebrafish and mouse that we show are not caused by loss of protein function. We find that the increase in transcript levels is due to enhanced transcription, and observe a correlation between the levels of mutant mRNA decay and transcriptional upregulation of related genes. To assess the role of mutant mRNA degradation in triggering transcriptional adaptation, we use genetic and pharmacological approaches and find that mRNA degradation is indeed required for this process. Notably, uncapped RNAs, themselves subjected to rapid degradation, can also induce transcriptional adaptation. Next, we generate alleles that fail to transcribe the mutated gene and find that they do not show transcriptional adaptation, and exhibit more severe phenotypes than those observed in alleles displaying mutant mRNA decay. Transcriptome analysis of these different alleles reveals the upregulation of hundreds of genes with enrichment for those showing sequence similarity with the mutated gene’s mRNA, suggesting a model whereby mRNA degradation products induce the response via sequence similarity. These results expand the role of the mRNA surveillance machinery in buffering against mutations by triggering the transcriptional upregulation of related genes. Besides implications for our understanding of disease-causing mutations, our findings will help design mutant alleles with minimal transcriptional adaptation-derived compensation.

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