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Molekuliarnaia Biologiia 2020RNA is a crucial component of every living organism and is necessary for gene expression and its regulation in the cell. Mechanisms of RNA synthesis (especially mRNA... (Review)
Review
RNA is a crucial component of every living organism and is necessary for gene expression and its regulation in the cell. Mechanisms of RNA synthesis (especially mRNA synthesis) were a subject of extensive study for a long time. More recently, RNA degradation pathways began to be considered as equally important part of eukaryotic cell metabolism. These pathways have been studied intensely, and ample information accumulated about RNA degradation systems and their role in cell life. It is currently obvious that RNA decay is of no less importance as RNA synthesis and contributes to regulating the RNA level in the cell. The review considers the main RNA degradation enzymes, the decay pathways of various coding and non-coding RNAs, the mechanisms providing RNA quality control in the nucleus and cytoplasm, and certain structural elements responsible for RNA stability or short life in the cell.
Topics: Cell Nucleus; Cytoplasm; Eukaryotic Cells; RNA; RNA Stability; Transcription, Genetic
PubMed: 32799219
DOI: 10.31857/S0026898420040163 -
Nature Structural & Molecular Biology Mar 2023RNA turnover pathways ensure appropriate gene expression levels by eliminating unwanted transcripts. Dis3-like 2 (Dis3L2) is a 3'-5' exoribonuclease that plays a...
RNA turnover pathways ensure appropriate gene expression levels by eliminating unwanted transcripts. Dis3-like 2 (Dis3L2) is a 3'-5' exoribonuclease that plays a critical role in human development. Dis3L2 independently degrades structured substrates, including coding and noncoding 3' uridylated RNAs. While the basis for Dis3L2's substrate recognition has been well characterized, the mechanism of structured RNA degradation by this family of enzymes is unknown. We characterized the discrete steps of the degradation cycle by determining cryogenic electron microscopy structures representing snapshots along the RNA turnover pathway and measuring kinetic parameters for RNA processing. We discovered a dramatic conformational change that is triggered by double-stranded RNA (dsRNA), repositioning two cold shock domains by 70 Å. This movement exposes a trihelix linker region, which acts as a wedge to separate the two RNA strands. Furthermore, we show that the trihelix linker is critical for dsRNA, but not single-stranded RNA, degradation. These findings reveal the conformational plasticity of Dis3L2 and detail a mechanism of structured RNA degradation.
Topics: Humans; RNA; RNA, Untranslated; Exoribonucleases; RNA Processing, Post-Transcriptional; RNA Stability; RNA, Double-Stranded
PubMed: 36823385
DOI: 10.1038/s41594-023-00923-x -
American Journal of Physiology. Cell... Oct 2020MicroRNAs (miRNAs) are short, noncoding RNAs that are evolutionarily conserved across many different species. miRNA regulation of gene expression, specifically in the... (Review)
Review
MicroRNAs (miRNAs) are short, noncoding RNAs that are evolutionarily conserved across many different species. miRNA regulation of gene expression, specifically in the context of the mammalian brain, has been well characterized; however, the regulation of miRNA degradation is still a focus of ongoing research. This review focuses on recent findings concerning the cellular mechanisms that govern miRNA degradation, with an emphasis on target-mediated miRNA degradation and how this phenomenon is uniquely poised to maintain homeostasis in neuronal systems.
Topics: Animals; Brain; Homeostasis; Humans; Mammals; MicroRNAs; Neurons; RNA Stability
PubMed: 32783657
DOI: 10.1152/ajpcell.00303.2020 -
Critical Reviews in Biochemistry and... Apr 2017Circular RNAs (CircRNAs) were first identified as a viroid and later found to also be an endogenous RNA splicing product in eukaryotes. In recent years, a series of... (Review)
Review
Circular RNAs (CircRNAs) were first identified as a viroid and later found to also be an endogenous RNA splicing product in eukaryotes. In recent years, a series of RNA-sequencing analyses from a diverse range of eukaryotes have shed new light on these eukaryotic circRNAs, revealing dynamic expression patterns in various developmental stages and physiological conditions. In this review, we focus on circRNAs implicated in stress response pathways and explore potential mechanisms underlying their regulation. To date, circRNAs have been shown to act as scaffolds in the assembly of protein complexes, sequester proteins from native subcellular localization, activate transcription of parental genes, inhibit RNA-protein interactions, and function as regulators of microRNA activity. Although the mechanism modulating circRNA levels during stress remains unclear, circRNAs are shown to be regulated during biogenesis, degradation, and exportation. As circRNAs do not have 5' and 3' ends, there are no entry points for exoribonucleases to initiate degradation. Such inherent stability makes this class of RNA a strong candidate to maintain homeostasis in the face of environmental challenges.
Topics: Animals; Cell Cycle; Cell Proliferation; Gene Expression Regulation; Humans; RNA; RNA Stability; RNA, Circular; Stress, Physiological; Transcription, Genetic
PubMed: 28095716
DOI: 10.1080/10409238.2016.1276882 -
Cellular and Molecular Life Sciences :... Mar 2021As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs... (Review)
Review
As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs including miRNAs have long been considered undruggable, and most efforts have been devoted to using synthetic oligonucleotides to regulate miRNAs. Encouragingly, recent findings have revealed that miRNAs can also be drugged with small molecules that directly target miRNAs. In this review paper, we give a summary of recently emerged small-molecule inhibitors (SMIs) and small-molecule degraders (SMDs) for miRNAs. SMIs are small molecules that directly bind to miRNAs to inhibit their biogenesis, and SMDs are bifunctional small molecules that upon binding to miRNAs induce miRNA degradation. Strategies for discovering SMIs and developing SMDs were summarized. Applications of SMIs and SMDs in miRNA inhibition and cancer therapy were also introduced. Overall, SMIs and SMDs introduced here have high potency and specificity in miRNA inhibition. We envision that these small molecules will pave the way for developing novel therapeutics toward miRNAs that were previously considered undruggable.
Topics: Animals; Gene Expression Regulation; High-Throughput Screening Assays; Humans; MicroRNAs; Molecular Structure; Nucleic Acid Conformation; RNA Stability; Small Molecule Libraries
PubMed: 33052435
DOI: 10.1007/s00018-020-03676-8 -
International Journal of Molecular... May 2019Although the large majority of mitochondrial proteins are nuclear encoded, for their correct functioning mitochondria require the expression of 13 proteins, two rRNA,... (Review)
Review
Although the large majority of mitochondrial proteins are nuclear encoded, for their correct functioning mitochondria require the expression of 13 proteins, two rRNA, and 22 tRNA codified by mitochondrial DNA (mtDNA). Once transcribed, mitochondrial RNA (mtRNA) is processed, mito-ribosomes are assembled, and mtDNA-encoded proteins belonging to the respiratory chain are synthesized. These processes require the coordinated spatio-temporal action of several enzymes, and many different factors are involved in the regulation and control of protein synthesis and in the stability and turnover of mitochondrial RNA. In this review, we describe the essential steps of mitochondrial RNA synthesis, maturation, and degradation, the factors controlling these processes, and how the alteration of these processes is associated with human pathologies.
Topics: Animals; Humans; Mitochondrial Diseases; RNA Processing, Post-Transcriptional; RNA Stability; RNA, Mitochondrial
PubMed: 31064115
DOI: 10.3390/ijms20092221 -
Wiley Interdisciplinary Reviews. RNA May 2019Cells must dynamically adapt to altered environmental conditions, particularly during times of stress, to ensure their ability to function effectively and survive. The... (Review)
Review
Cells must dynamically adapt to altered environmental conditions, particularly during times of stress, to ensure their ability to function effectively and survive. The macroautophagy/autophagy pathway is highly conserved across eukaryotic cells and promotes cell survival during stressful conditions. In general, basal autophagy occurs at a low level to sustain cellular homeostasis and metabolism. However, autophagy is robustly upregulated in response to nutrient deprivation, pathogen infection and increased accumulation of potentially toxic protein aggregates and superfluous organelles. Within the cell, RNA decay maintains quality control to remove aberrant transcripts and regulate appropriate levels of gene expression. Recent evidence has identified components of the cellular mRNA decay machinery as novel regulators of autophagy. Here, we review current findings that demonstrate how autophagy is modulated through RNA decay. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability.
Topics: Autophagy; Eukaryotic Cells; Gene Expression Regulation; RNA Stability; Stress, Physiological
PubMed: 30560575
DOI: 10.1002/wrna.1522 -
Journal of Zhejiang University.... May 2014Eukaryotic gene expression is controlled by different levels of biological events, such as transcription factors regulating the timing and strength of transcripts... (Review)
Review
Eukaryotic gene expression is controlled by different levels of biological events, such as transcription factors regulating the timing and strength of transcripts production, alteration of transcription rate by RNA processing, and mRNA stability during RNA processing and translation. RNAs, especially mRNAs, are relatively vulnerable molecules in living cells for ribonucleases (RNases). The maintenance of quality and quantity of transcripts is a key issue for many biological processes. Extensive studies draw the conclusion that the stability of RNAs is dedicated-regulated, occurring co- and post-transcriptionally, and translation-coupled as well, either in the nucleus or cytoplasm. Recently, RNA stability in the nucleus has aroused much research interest, especially the stability of newly-made transcripts. In this article, we summarize recent progresses on mRNA stability in the nucleus, especially focusing on quality control of newly-made RNA by RNA polymerase II in eukaryotes.
Topics: Animals; Cell Nucleus; DNA-Directed RNA Polymerases; Epigenesis, Genetic; Gene Expression Regulation; Humans; Models, Genetic; RNA Stability; RNA, Messenger; Transcription, Genetic; Transcriptional Activation
PubMed: 24793762
DOI: 10.1631/jzus.B1400088 -
Virology May 2015Viral replication significantly alters the gene expression landscape of infected cells. Many of these changes are driven by viral manipulation of host transcription or... (Review)
Review
Viral replication significantly alters the gene expression landscape of infected cells. Many of these changes are driven by viral manipulation of host transcription or translation machinery. Several mammalian viruses encode factors that broadly dampen gene expression by directly targeting messenger RNA (mRNA). Here, we highlight how these factors promote mRNA degradation to globally regulate both host and viral gene expression. Although these viral factors are not homologous and use distinct mechanisms to target mRNA, many of them display striking parallels in their strategies for executing RNA degradation and invoke key features of cellular RNA quality control pathways. In some cases, there is a lack of selectivity for degradation of host versus viral mRNA, indicating that the purposes of virus-induced mRNA degradation extend beyond redirecting cellular resources towards viral gene expression. In addition, several antiviral pathways use RNA degradation as a viral restriction mechanism, and we will summarize new findings related to how these host-encoded ribonucleases target and destroy viral RNA.
Topics: Host-Pathogen Interactions; RNA Stability; RNA, Messenger; RNA, Viral; Virus Physiological Phenomena; Virus Replication; Viruses
PubMed: 25721579
DOI: 10.1016/j.virol.2015.02.007 -
Genomics Jul 2022RNA sequencing is an innovative technology to study transcriptomes in both biological and clinical research. However, clinical specimens from patients undergoing...
RNA sequencing is an innovative technology to study transcriptomes in both biological and clinical research. However, clinical specimens from patients undergoing surgical operations have a major challenge due to sample degradation. This study replicated the process of RNA degradation by maintaining cells at room temperature to achieve none, slight, middle, and high levels of RNA degradation with decreasing RNA integrity numbers (RIN) of approximately 9.8, 6.7, 4.4, and 2.5, respectively. Next, the differential expression of mRNA and long non-coding RNA (lncRNA) was analyzed in the four degradation groups along with pathway enrichment analysis. The results showed that the similarity of lncRNAs exhibited significant differences even for a slight level of RNA degradation compared with the non-degraded RNA sample. Also, the RNA degradation process was found to be universal, global, and random; the differentially expressed genes increased with an increase in degradation but the pathway enrichment phenomenon was not significantly observed.
Topics: Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; RNA Stability; RNA, Long Noncoding; Sequence Analysis, RNA; Transcriptome
PubMed: 35810931
DOI: 10.1016/j.ygeno.2022.110429