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Interplay between Pre-mRNA Splicing and Other Gene Expression Steps in Eukaryotes 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 45201

Special Issue Editor


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Guest Editor
Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, Tokyo, Japan
Interests: pre-mRNA splicing; RNA processing; RNA diseases; gene expression; molecular links between mRNA splicing and other gene expression steps; signal transduction modulated by alternative splicing
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Special Issue Information

Dear Colleagues,

In eukaryotes, RNAs transcribed from genomic DNA are subjected to many regulatory processes, indicating their pivotal role in gene expression. Pre-mRNA splicing is a process to remove introns and ligate exons so that mRNA can be produced. This step is critical for higher eukaryotes and is vigorously regulated. After finding the Exon Junction Complex, several lines of evidence have noted that pre-mRNA splicing and other gene expression steps have influence over each other and there is an interplay between pre-mRNA splicing and other gene expression in higher eukaryotes.

As the Guest Editor of this Special Issue, “Interplay between Pre-mRNA Splicing and Other Gene Expression Steps in Eukaryotes”, in IJMS, I expect submissions from many researchers working on the wide spectrum of physiological processes in which RNAs are involved. The focus of this topic is the molecular link between pre-mRNA splicing and other steps in eukaryotes. Examples for this Special Issue include transcription-coupled splicing, coupling of splicing and mRNA export/localization, nonsense-mediated mRNA decay, enhancement of translation, and signal transduction pathway modulation by alternative splicing. Manuscripts regarding splicing changes during the development of organisms and aberrant splicing in human diseases are also very welcome. The formats for submissions include original research reports, reviews, perspectives/opinions and methodology articles.

Dr. Naoyuki Kataoka
Guest Editor

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Keywords

  • Pre-mRNA splicing
  • Exon Junction Complex
  • alternative splicing
  • transcription
  • translation
  • RNA export
  • RNA localization
  • RNA decay

Published Papers (10 papers)

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Research

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18 pages, 2719 KiB  
Article
Titration of SF3B1 Activity Reveals Distinct Effects on the Transcriptome and Cell Physiology
by Karen S. Kim Guisbert, Isiah Mossiah and Eric Guisbert
Int. J. Mol. Sci. 2020, 21(24), 9641; https://doi.org/10.3390/ijms21249641 - 17 Dec 2020
Cited by 2 | Viewed by 2352
Abstract
SF3B1 is a core component of the U2 spliceosome that is frequently mutated in cancer. We have previously shown that titrating the activity of SF3B1, using the inhibitor pladienolide B (PB), affects distinct steps of the heat shock response (HSR). Here, we identify [...] Read more.
SF3B1 is a core component of the U2 spliceosome that is frequently mutated in cancer. We have previously shown that titrating the activity of SF3B1, using the inhibitor pladienolide B (PB), affects distinct steps of the heat shock response (HSR). Here, we identify other genes that are sensitive to different levels of SF3B1 (5 vs. 100 nM PB) using RNA sequencing. Significant changes to mRNA splicing were identified at both low PB and high PB concentrations. Changes in expression were also identified in the absence of alternative splicing, suggesting that SF3B1 influences other gene expression pathways. Surprisingly, gene expression changes identified in low PB are not predictive of changes in high PB. Specific pathways were identified with differential sensitivity to PB concentration, including nonsense-mediated decay and protein-folding homeostasis, both of which were validated using independent reporter constructs. Strikingly, cells exposed to low PB displayed enhanced protein-folding capacity relative to untreated cells. These data reveal that the transcriptome is exquisitely sensitive to SF3B1 and suggests that the activity of SF3B1 is finely regulated to coordinate mRNA splicing, gene expression and cellular physiology. Full article
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13 pages, 13183 KiB  
Article
Rbm38 Reduces the Transcription Elongation Defect of the SMEK2 Gene Caused by Splicing Deficiency
by Shintaro Muraoka, Kazuhiro Fukumura, Megumi Hayashi, Naoyuki Kataoka, Akila Mayeda and Daisuke Kaida
Int. J. Mol. Sci. 2020, 21(22), 8799; https://doi.org/10.3390/ijms21228799 - 20 Nov 2020
Cited by 2 | Viewed by 3008
Abstract
Pre-mRNA splicing is an essential mechanism for ensuring integrity of the transcriptome in eukaryotes. Therefore, splicing deficiency might cause a decrease in functional proteins and the production of nonfunctional, aberrant proteins. To prevent the production of such aberrant proteins, eukaryotic cells have several [...] Read more.
Pre-mRNA splicing is an essential mechanism for ensuring integrity of the transcriptome in eukaryotes. Therefore, splicing deficiency might cause a decrease in functional proteins and the production of nonfunctional, aberrant proteins. To prevent the production of such aberrant proteins, eukaryotic cells have several mRNA quality control mechanisms. In addition to the known mechanisms, we previously found that transcription elongation is attenuated to prevent the accumulation of pre-mRNA under splicing-deficient conditions. However, the detailed molecular mechanism behind the defect in transcription elongation remains unknown. Here, we showed that the RNA binding protein Rbm38 reduced the transcription elongation defect of the SMEK2 gene caused by splicing deficiency. This reduction was shown to require the N- and C-terminal regions of Rbm38, along with an important role being played by the RNA-recognition motif of Rbm38. These findings advance our understanding of the molecular mechanism of the transcription elongation defect caused by splicing deficiency. Full article
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Review

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21 pages, 1565 KiB  
Review
Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay
by Juan F. García-Moreno and Luísa Romão
Int. J. Mol. Sci. 2020, 21(24), 9424; https://doi.org/10.3390/ijms21249424 - 10 Dec 2020
Cited by 35 | Viewed by 5371
Abstract
Alternative splicing (AS) of precursor mRNA (pre-mRNA) is a cellular post-transcriptional process that generates protein isoform diversity. Nonsense-mediated RNA decay (NMD) is an mRNA surveillance pathway that recognizes and selectively degrades transcripts containing premature translation-termination codons (PTCs), thereby preventing the production of truncated [...] Read more.
Alternative splicing (AS) of precursor mRNA (pre-mRNA) is a cellular post-transcriptional process that generates protein isoform diversity. Nonsense-mediated RNA decay (NMD) is an mRNA surveillance pathway that recognizes and selectively degrades transcripts containing premature translation-termination codons (PTCs), thereby preventing the production of truncated proteins. Nevertheless, NMD also fine-tunes the gene expression of physiological mRNAs encoding full-length proteins. Interestingly, around one third of all AS events results in PTC-containing transcripts that undergo NMD. Numerous studies have reported a coordinated action between AS and NMD, in order to regulate the expression of several genes, especially those coding for RNA-binding proteins (RBPs). This coupling of AS to NMD (AS-NMD) is considered a gene expression tool that controls the ratio of productive to unproductive mRNA isoforms, ultimately degrading PTC-containing non-functional mRNAs. In this review, we focus on the mechanisms underlying AS-NMD, and how this regulatory process is able to control the homeostatic expression of numerous RBPs, including splicing factors, through auto- and cross-regulatory feedback loops. Furthermore, we discuss the importance of AS-NMD in the regulation of biological processes, such as cell differentiation. Finally, we analyze interesting recent data on the relevance of AS-NMD to human health, covering its potential roles in cancer and other disorders. Full article
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19 pages, 1037 KiB  
Review
Temperature-Dependent Alternative Splicing of Precursor mRNAs and Its Biological Significance: A Review Focused on Post-Transcriptional Regulation of a Cold Shock Protein Gene in Hibernating Mammals
by Takahiko Shiina and Yasutake Shimizu
Int. J. Mol. Sci. 2020, 21(20), 7599; https://doi.org/10.3390/ijms21207599 - 14 Oct 2020
Cited by 9 | Viewed by 3485
Abstract
Multiple mRNA isoforms are often generated during processing such as alternative splicing of precursor mRNAs (pre-mRNA), resulting in a diversity of generated proteins. Alternative splicing is an essential mechanism for the functional complexity of eukaryotes. Temperature, which is involved in all life activities [...] Read more.
Multiple mRNA isoforms are often generated during processing such as alternative splicing of precursor mRNAs (pre-mRNA), resulting in a diversity of generated proteins. Alternative splicing is an essential mechanism for the functional complexity of eukaryotes. Temperature, which is involved in all life activities at various levels, is one of regulatory factors for controlling patterns of alternative splicing. Temperature-dependent alternative splicing is associated with various phenotypes such as flowering and circadian clock in plants and sex determination in poikilothermic animals. In some specific situations, temperature-dependent alternative splicing can be evoked even in homothermal animals. For example, the splicing pattern of mRNA for a cold shock protein, cold-inducible RNA-binding protein (CIRP or CIRBP), is changed in response to a marked drop in body temperature during hibernation of hamsters. In this review, we describe the current knowledge about mechanisms and functions of temperature-dependent alternative splicing in plants and animals. Then we discuss the physiological significance of hypothermia-induced alternative splicing of a cold shock protein gene in hibernating and non-hibernating animals. Full article
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12 pages, 682 KiB  
Review
Role of Arginine Methylation in Alternative Polyadenylation of VEGFR-1 (Flt-1) pre-mRNA
by Takayuki Ikeda, Hidehito Saito-Takatsuji, Yasuo Yoshitomi and Hideto Yonekura
Int. J. Mol. Sci. 2020, 21(18), 6460; https://doi.org/10.3390/ijms21186460 - 4 Sep 2020
Cited by 5 | Viewed by 3390
Abstract
Mature mRNA is generated by the 3ʹ end cleavage and polyadenylation of its precursor pre-mRNA. Eukaryotic genes frequently have multiple polyadenylation sites, resulting in mRNA isoforms with different 3ʹ-UTR lengths that often encode different C-terminal amino acid sequences. It is well-known that this [...] Read more.
Mature mRNA is generated by the 3ʹ end cleavage and polyadenylation of its precursor pre-mRNA. Eukaryotic genes frequently have multiple polyadenylation sites, resulting in mRNA isoforms with different 3ʹ-UTR lengths that often encode different C-terminal amino acid sequences. It is well-known that this form of post-transcriptional modification, termed alternative polyadenylation, can affect mRNA stability, localization, translation, and nuclear export. We focus on the alternative polyadenylation of pre-mRNA for vascular endothelial growth factor receptor-1 (VEGFR-1), the receptor for VEGF. VEGFR-1 is a transmembrane protein with a tyrosine kinase in the intracellular region. Secreted forms of VEGFR-1 (sVEGFR-1) are also produced from the same gene by alternative polyadenylation, and sVEGFR-1 has a function opposite to that of VEGFR-1 because it acts as a decoy receptor for VEGF. However, the mechanism that regulates the production of sVEGFR-1 by alternative polyadenylation remains poorly understood. In this review, we introduce and discuss the mechanism of alternative polyadenylation of VEGFR-1 mediated by protein arginine methylation. Full article
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21 pages, 1235 KiB  
Review
Computational Methods for Predicting Functions at the mRNA Isoform Level
by Sambit K. Mishra, Viraj Muthye and Gaurav Kandoi
Int. J. Mol. Sci. 2020, 21(16), 5686; https://doi.org/10.3390/ijms21165686 - 8 Aug 2020
Cited by 4 | Viewed by 4256
Abstract
Multiple mRNA isoforms of the same gene are produced via alternative splicing, a biological mechanism that regulates protein diversity while maintaining genome size. Alternatively spliced mRNA isoforms of the same gene may sometimes have very similar sequence, but they can have significantly diverse [...] Read more.
Multiple mRNA isoforms of the same gene are produced via alternative splicing, a biological mechanism that regulates protein diversity while maintaining genome size. Alternatively spliced mRNA isoforms of the same gene may sometimes have very similar sequence, but they can have significantly diverse effects on cellular function and regulation. The products of alternative splicing have important and diverse functional roles, such as response to environmental stress, regulation of gene expression, human heritable, and plant diseases. The mRNA isoforms of the same gene can have dramatically different functions. Despite the functional importance of mRNA isoforms, very little has been done to annotate their functions. The recent years have however seen the development of several computational methods aimed at predicting mRNA isoform level biological functions. These methods use a wide array of proteo-genomic data to develop machine learning-based mRNA isoform function prediction tools. In this review, we discuss the computational methods developed for predicting the biological function at the individual mRNA isoform level. Full article
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35 pages, 1437 KiB  
Review
Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control
by Katarzyna Taylor and Krzysztof Sobczak
Int. J. Mol. Sci. 2020, 21(14), 5161; https://doi.org/10.3390/ijms21145161 - 21 Jul 2020
Cited by 16 | Viewed by 4852
Abstract
Alternative splicing is a highly sophisticated process, playing a significant role in posttranscriptional gene expression and underlying the diversity and complexity of organisms. Its regulation is multilayered, including an intrinsic role of RNA structural arrangement which undergoes time- and tissue-specific alterations. In this [...] Read more.
Alternative splicing is a highly sophisticated process, playing a significant role in posttranscriptional gene expression and underlying the diversity and complexity of organisms. Its regulation is multilayered, including an intrinsic role of RNA structural arrangement which undergoes time- and tissue-specific alterations. In this review, we describe the principles of RNA structural arrangement and briefly decipher its cis- and trans-acting cellular modulators which serve as crucial determinants of biological functionality of the RNA structure. Subsequently, we engage in a discussion about the RNA structure-mediated mechanisms of alternative splicing regulation. On one hand, the impairment of formation of optimal RNA structures may have critical consequences for the splicing outcome and further contribute to understanding the pathomechanism of severe disorders. On the other hand, the structural aspects of RNA became significant features taken into consideration in the endeavor of finding potential therapeutic treatments. Both aspects have been addressed by us emphasizing the importance of ongoing studies in both fields. Full article
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27 pages, 6501 KiB  
Review
Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds
by Ken-ichi Fujita, Takaki Ishizuka, Mizuki Mitsukawa, Masashi Kurata and Seiji Masuda
Int. J. Mol. Sci. 2020, 21(6), 2026; https://doi.org/10.3390/ijms21062026 - 16 Mar 2020
Cited by 8 | Viewed by 5375
Abstract
Human transcriptomes are more divergent than genes and contribute to the sophistication of life. This divergence is derived from various isoforms arising from alternative splicing. In addition, alternative splicing regulated by spliceosomal factors and RNA structures, such as the RNA G-quadruplex, is important [...] Read more.
Human transcriptomes are more divergent than genes and contribute to the sophistication of life. This divergence is derived from various isoforms arising from alternative splicing. In addition, alternative splicing regulated by spliceosomal factors and RNA structures, such as the RNA G-quadruplex, is important not only for isoform diversity but also for regulating gene expression. Therefore, abnormal splicing leads to serious diseases such as cancer and neurodegenerative disorders. In the first part of this review, we describe the regulation of divergent transcriptomes using alternative mRNA splicing. In the second part, we present the relationship between the disruption of splicing and diseases. Recently, various compounds with splicing inhibitor activity were established. These splicing inhibitors are recognized as a biological tool to investigate the molecular mechanism of splicing and as a potential therapeutic agent for cancer treatment. Food-derived compounds with similar functions were found and are expected to exhibit anticancer effects. In the final part, we describe the compounds that modulate the messenger RNA (mRNA) splicing process and their availability for basic research and future clinical potential. Full article
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20 pages, 2059 KiB  
Review
Roles of Splicing Factors in Hormone-Related Cancer Progression
by Toshihiko Takeiwa, Yuichi Mitobe, Kazuhiro Ikeda, Kuniko Horie-Inoue and Satoshi Inoue
Int. J. Mol. Sci. 2020, 21(5), 1551; https://doi.org/10.3390/ijms21051551 - 25 Feb 2020
Cited by 16 | Viewed by 3782
Abstract
Splicing of mRNA precursor (pre-mRNA) is a mechanism to generate multiple mRNA isoforms from a single pre-mRNA, and it plays an essential role in a variety of biological phenomena and diseases such as cancers. Previous studies have demonstrated that cancer-specific splicing events are [...] Read more.
Splicing of mRNA precursor (pre-mRNA) is a mechanism to generate multiple mRNA isoforms from a single pre-mRNA, and it plays an essential role in a variety of biological phenomena and diseases such as cancers. Previous studies have demonstrated that cancer-specific splicing events are involved in various aspects of cancers such as proliferation, migration and response to hormones, suggesting that splicing-targeting therapy can be promising as a new strategy for cancer treatment. In this review, we focus on the splicing regulation by RNA-binding proteins including Drosophila behavior/human splicing (DBHS) family proteins, serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) in hormone-related cancers, such as breast and prostate cancers. Full article
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14 pages, 5252 KiB  
Review
Mechanisms and Regulation of Nonsense-Mediated mRNA Decay and Nonsense-Associated Altered Splicing in Lymphocytes
by Jean-Marie Lambert, Mohamad Omar Ashi, Nivine Srour, Laurent Delpy and Jérôme Saulière
Int. J. Mol. Sci. 2020, 21(4), 1335; https://doi.org/10.3390/ijms21041335 - 17 Feb 2020
Cited by 9 | Viewed by 8288
Abstract
The presence of premature termination codons (PTCs) in transcripts is dangerous for the cell as they encode potentially deleterious truncated proteins that can act with dominant-negative or gain-of-function effects. To avoid the synthesis of these shortened polypeptides, several RNA surveillance systems can be [...] Read more.
The presence of premature termination codons (PTCs) in transcripts is dangerous for the cell as they encode potentially deleterious truncated proteins that can act with dominant-negative or gain-of-function effects. To avoid the synthesis of these shortened polypeptides, several RNA surveillance systems can be activated to decrease the level of PTC-containing mRNAs. Nonsense-mediated mRNA decay (NMD) ensures an accelerated degradation of mRNAs harboring PTCs by using several key NMD factors such as up-frameshift (UPF) proteins. Another pathway called nonsense-associated altered splicing (NAS) upregulates transcripts that have skipped disturbing PTCs by alternative splicing. Thus, these RNA quality control processes eliminate abnormal PTC-containing mRNAs from the cells by using positive and negative responses. In this review, we describe the general mechanisms of NMD and NAS and their respective involvement in the decay of aberrant immunoglobulin and TCR transcripts in lymphocytes. Full article
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