Eukaryotic mRNA Decay: Methodologies, Pathways, and Links to Other Stages of Gene Expression (original) (raw)
Related papers
Genome-wide studies of mRNA synthesis and degradation in eukaryotes
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2012
In recent years, the use of genome-wide technologies has revolutionized the study of eukaryotic transcription producing results for thousands of genes at every step of mRNA life. The statistical analyses of the results for a single condition, different conditions, different transcription stages, or even between different techniques, is outlining a totally new landscape of the eukaryotic transcription process. Although most studies have been conducted in the yeast Saccharomyces cerevisiae as a model cell, others have also focused on higher eukaryotes, which can also be comparatively analyzed. The picture which emerges is that transcription is a more variable process than initially suspected, with large differences between genes at each stage of the process, from initiation to mRNA degradation, but with striking similarities for functionally related genes, indicating that all steps are coordinately regulated. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.
RNA decay modulates gene expression and controls its fidelity
2010
Maintenance of cellular function relies on the expression of genetic information with high fidelity, a process in which RNA molecules form an important link. mRNAs are intermediates that define the proteome, rRNAs and tRNAs are effector molecules that act together to decode mRNA sequence information, and small noncoding RNAs can regulate mRNA half-life and translatability. The steady-state levels of these RNAs occur through transcriptional and posttranscriptional regulatory mechanisms, of which RNA decay pathways are integral components. RNA decay can initiate from the ends of a transcript or through endonucleolytic cleavage, and numerous factors that catalyze or promote these reactions have been identified and characterized. The rate at which decay occurs depends on RNA sequence or structural elements and usually requires the RNA to be modified in a way that allows recruitment of the decay machinery to the transcript through the binding of accessory factors or small RNAs. The major RNA decay pathways also play important roles in the quality control of gene expression. Acting in both the nucleus and cytoplasm, multiple quality control factors monitor newly synthesized transcripts, or mRNAs undergoing translation, for properties essential to function, including structural integrity or the presence of complete open reading frames. Transcripts targeted by these surveillance mechanisms are rapidly shunted into conventional decay pathways where they are degraded rapidly to ensure that they do not interfere with the normal course of gene expression. Collectively, degradative mechanisms are important determinants of the extent of gene expression and play key roles in maintaining its accuracy.
Gene Expression Is Circular: Factors for mRNA Degradation Also Foster mRNA Synthesis
Cell, 2013
Maintaining the proper level of mRNAs is a key aspect in the regulation of gene expression. The balance between mRNA synthesis and decay determines these levels. Using a whole-genome analysis, we demonstrate that most yeast mRNAs are degraded by the 5' to 3' pathway (the "decaysome"), as proposed previously. Unexpectedly, the level of these mRNAs is highly robust to perturbations in this major pathway, as defects in various decaysome components lead to downregulation of transcription. Moreover, these components shuttle between the cytoplasm and the nucleus, in a manner dependent on proper mRNA degradation; in the nucleus, they associate with chromatin and directly stimulate transcription initiation and elongation. Hence, the major decaysome has a dual role in maintaining mRNA levels. Significantly, proper import of some decaysome components seems to play a key role in coupling the two functions. Gene expression process is therefore circular, whereby the hitherto first and last stages are interconnected.
Regulation of cytoplasmic mRNA decay
Nature Reviews Genetics, 2012
Discoveries made over the past 20 years highlight the importance of mRNA decay as a means to modulate gene expression and thereby protein production. Up until recently, studies focused largely on identifying cis-acting sequences that serve as mRNA stability or instability elements, the proteins that bind these elements, how the process of translation influences mRNA decay, and the ribonucleases that catalyze decay. Now, current studies have begun to elucidate how the decay process is regulated. This review examines our current understanding of how mammalian-cell mRNA decay is controlled by different signaling pathways and lays out a framework for future research.
The intimate relationships of mRNA decay and translation
Trends in Genetics, 2013
The decay rate of an mRNA and the efficiency with which it is translated are key determinants of eukaryotic gene expression. Although it was once thought that mRNA stability and translational efficiency were directly linked, the interrelationships between the two processes are considerably more complex. The decay of individual mRNAs can be triggered or antagonized by translational impairment, and alterations in the half-life of certain mRNAs can even alter translational fidelity. In this review we consider whether mRNA translation and turnover are distinct or overlapping phases of an mRNA life cycle, and then address some of the many ways in which the two processes influence each other in eukaryotic cells.
Nature Communications, 2022
mRNA level is controlled by factors that mediate both mRNA synthesis and decay, including the 5' to 3' exonuclease Xrn1. Here we show that nucleocytoplasmic shuttling of several yeast mRNA decay factors plays a key role in determining both mRNA synthesis and decay. Shuttling is regulated by RNAcontrolled binding of the karyopherin Kap120 to two nuclear localization sequences (NLSs) in Xrn1, location of one of which is conserved from yeast to human. The decaying RNA binds and masks NLS1, establishing a link between mRNA decay and Xrn1 shuttling. Preventing Xrn1 import, either by deleting KAP120 or mutating the two Xrn1 NLSs, compromises transcription and, unexpectedly, also cytoplasmic decay, uncovering a cytoplasmic decay pathway that initiates in the nucleus. Most mRNAs are degraded by both pathwaysthe ratio between them represents a full spectrum. Importantly, Xrn1 shuttling is required for proper responses to environmental changes, e.g., fluctuating temperatures, involving proper changes in mRNA abundance and in cell proliferation rate. A high degree of regulation of mRNA levels is a critical feature of gene expression in any living organism. In recent years, we and other investigators have discovered reciprocal adjustments between the overall rates of mRNA synthesis and degradation, named "mRNA buffering", which maintain proper concentrations of mRNAs 1-7. We have previously demonstrated that in the budding yeast Saccharomyces cerevisiae (from herein termed "yeast"), a number of factors, known to regulate or execute mRNA degradation in the cytoplasm, e.g., Xrn1 (alias-Kem1), Dcp2, Pat1, Lsm1 8,9 , shuttle between the nucleus and the cytoplasm, by an unknown mechanism 3. The mRNA buffering mechanism is not restricted to factors recognized as mRNA decay factors (DFs). It also includes components of the transcription apparatus. We demonstrated that Pol II regulates mRNA translation and decay by mediating Rpb4/7 co-transcriptional binding to Pol II transcripts 10-12 , a process we named "mRNA imprinting" 13,14. More "classical" yeast DFscomponents of the Ccr4-Not complex-also imprint mRNA and regulate mRNA export, translation and decay 15,16. Even a promoter-specific transcription factor, Rap1, can control mRNA decay via mRNA imprinting 17. Thus, we hypothesize that mechanisms that regulate the cellular localization of factors that mediate mRNA
Gene regulation by synergism between mRNA decay and gene transcription
It has become increasingly clear in the last few years that gene expression in eukaryotes is not a linear process starting from transcription in the nucleus to the cytoplasm, but a circular one where the mRNA level is controlled by crosstalk between nuclear transcription and cytoplasmic decay pathways. One of the possible purposes of this crosstalk is to keep the mRNA level approximately constant. This is called mRNA buffering and happens when transcription and mRNA degradation act at compensatory rates. However, if transcription and mRNA degradation act synergistically, enhanced gene expression regulation would occur. In this work we mathematically modeled the effects of RNA binding proteins (RBP) when they have positive or negative effects on mRNA synthesis and decay rates. We found that they can buffer or enhance gene expression responses depending on their respective effects on transcription and mRNA stability. Then we analyzed new and previously published genomic datasets obtai...
Mechanisms of mRNA degradation in eukaryotes
Trends in Biochemical Sciences, 1994
role, but not in its enzyme acti~ty. The implication is that PD! has an essential role that is distinct from its function in formation of native disulphides, but work on purified EUG1 is required to confirm this interpretation.