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Mechanism and Regulation of Pre-mRNA Splicing
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Mechanism and Regulation of Pre-mRNA Splicing

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 17814

Special Issue Editor

Prof. Dr. Akila Mayeda

E-Mail Website
Guest Editor
Division of Gene Expression Mechanism, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Interests: pre-mRNA splicing; mechanism of splicing; regulation of splicing; aberrant splicing in diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In eukaryotes, most gene transcripts or pre-mRNAs are interrupted by intervening sequences termed introns, which are precisely removed by a process called splicing. This process is essential since spliced mRNAs serve as templates for proteins. Regulation in the splicing process is certainly crucial for a wide variety of biological and physiological phenomena. The process is therefore highly discriminatory and faithful, and mis-regulation in this process causes disorders in cell functions, often with severe clinical consequences.

This Special Issue will cover, but is not limited to, the following topics:

*The mechanism and regulation of constitutive and alternative splicing;

*The mechanism and regulation of splicing-linked post-splicing processes;

*Pre-mRNA–protein interactions involved in splicing and splicing-linked processes;

*hnRNP/mRNP assembly and functions in splicing and splicing-linked processes;

*Evolutional studies of pre-mRNAs and splicing;

*Pre-mRNA processing in development and diseases including cancers.

Prof. Dr. Akila Mayeda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (7 papers)

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Research

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13 pages, 2835 KiB  
Article
Altered HIV-1 mRNA Splicing Due to Drug-Resistance-Associated Mutations in Exon 2/2b
by Lisa Müller, Wiebke Moskorz, Anna-Lena Brillen, Frank Hillebrand, Philipp Niklas Ostermann, Niklas Kiel, Lara Walotka, Johannes Ptok, Jörg Timm, Nadine Lübke and Heiner Schaal
Int. J. Mol. Sci. 2022, 23(1), 156; https://doi.org/10.3390/ijms23010156 - 23 Dec 2021
Cited by 1 | Viewed by 2088
Abstract
The underlying molecular mechanism and their general effect on the replication capacity of HIV 1 drug-resistance-associated mutations is often poorly understood. To elucidate the effect of two such mutations located in a region with a high density of spicing regulatory elements on the [...] Read more.
The underlying molecular mechanism and their general effect on the replication capacity of HIV 1 drug-resistance-associated mutations is often poorly understood. To elucidate the effect of two such mutations located in a region with a high density of spicing regulatory elements on the HIV-1-splicing outcome, bioinformatic predictions were combined with transfection and infection experiments. Results show that the previously described R263K drug-resistance-associated integrase mutation has additionally a severe effect on the ESE2b splicing regulatory element (SRE) in exon 2b, which causes loss of SD2b recognition. This was confirmed by an R263R silent mutation with a similar predicted effect on the exon 2b SRE. In contrast, a V260I mutation and its silent counterpart with a lower effect on ESS2b did not exhibit any differences in the splicing pattern. Since HIV-1 highly relies on a balanced splicing reaction, changes in the splicing outcome can contribute to changes in viral replication and might add to the effect of escape mutations toward antiviral drugs. Thus, a classification of mutations purely addressing proteins is insufficient. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Pre-mRNA Splicing)
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12 pages, 1921 KiB  
Article
A Deep Exon Cryptic Splice Site Promotes Aberrant Intron Retention in a Von Willebrand Disease Patient
by John G. Conboy
Int. J. Mol. Sci. 2021, 22(24), 13248; https://doi.org/10.3390/ijms222413248 - 09 Dec 2021
Cited by 3 | Viewed by 1765
Abstract
A translationally silent single nucleotide mutation in exon 44 (E44) of the von Willebrand factor (VWF) gene is associated with inefficient removal of intron 44 in a von Willebrand disease (VWD) patient. This intron retention (IR) event was previously attributed to reordered E44 [...] Read more.
A translationally silent single nucleotide mutation in exon 44 (E44) of the von Willebrand factor (VWF) gene is associated with inefficient removal of intron 44 in a von Willebrand disease (VWD) patient. This intron retention (IR) event was previously attributed to reordered E44 secondary structure that sequesters the normal splice donor site. We propose an alternative mechanism: the mutation introduces a cryptic splice donor site that interferes with the function of the annotated site to favor IR. We evaluated both models using minigene splicing reporters engineered to vary in secondary structure and/or cryptic splice site content. Analysis of splicing efficiency in transfected K562 cells suggested that the mutation-generated cryptic splice site in E44 was sufficient to induce substantial IR. Mutations predicted to vary secondary structure at the annotated site also had modest effects on IR and shifted the balance of residual splicing between the cryptic site and annotated site, supporting competition among the sites. Further studies demonstrated that introduction of cryptic splice donor motifs at other positions in E44 did not promote IR, indicating that interference with the annotated site is context dependent. We conclude that mutant deep exon splice sites can interfere with proper splicing by inducing IR. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Pre-mRNA Splicing)
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22 pages, 5530 KiB  
Article
The SR Splicing Factors: Providing Perspectives on Their Evolution, Expression, Alternative Splicing, and Function in Populus trichocarpa
by Xijuan Zhao, Lingling Tan, Shuo Wang, Yirong Shen, Liangyu Guo, Xiaoxue Ye, Shenkui Liu, Ying Feng and Wenwu Wu
Int. J. Mol. Sci. 2021, 22(21), 11369; https://doi.org/10.3390/ijms222111369 - 21 Oct 2021
Cited by 18 | Viewed by 2101
Abstract
Serine/arginine-rich (SR) proteins are important splicing factors in plant development and abiotic/hormone-related stresses. However, evidence that SR proteins contribute to the process in woody plants has been lacking. Using phylogenetics, gene synteny, transgenic experiments, and RNA-seq analysis, we identified 24 PtSR genes and [...] Read more.
Serine/arginine-rich (SR) proteins are important splicing factors in plant development and abiotic/hormone-related stresses. However, evidence that SR proteins contribute to the process in woody plants has been lacking. Using phylogenetics, gene synteny, transgenic experiments, and RNA-seq analysis, we identified 24 PtSR genes and explored their evolution, expression, and function in Popolus trichocarpa. The PtSR genes were divided into six subfamilies, generated by at least two events of genome triplication and duplication. Notably, they were constitutively expressed in roots, stems, and leaves, demonstrating their fundamental role in P. trichocarpa. Additionally, most PtSR genes (~83%) responded to at least one stress (cold, drought, salt, SA, MeJA, or ABA), and, especially, cold stress induced a dramatic perturbation in the expression and/or alternative splicing (AS) of 18 PtSR genes (~75%). Evidentially, the overexpression of PtSCL30 in Arabidopsis decreased freezing tolerance, which probably resulted from AS changes of the genes (e.g., ICE2 and COR15A) critical for cold tolerance. Moreover, the transgenic plants were salt-hypersensitive at the germination stage. These indicate that PtSCL30 may act as a negative regulator under cold and salt stress. Altogether, this study sheds light on the evolution, expression, and AS of PtSR genes, and the functional mechanisms of PtSCL30 in woody plants. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Pre-mRNA Splicing)
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14 pages, 1621 KiB  
Article
Sequestration of RBM10 in Nuclear Bodies: Targeting Sequences and Biological Significance
by Ling-Yu Wang, Sheng-Jun Xiao, Hiroyuki Kunimoto, Kazuaki Tokunaga, Hirotada Kojima, Masatsugu Kimura, Takahiro Yamamoto, Naoki Yamamoto, Hong Zhao, Koji Nishio, Tokio Tani, Koichi Nakajima, Kishiko Sunami and Akira Inoue
Int. J. Mol. Sci. 2021, 22(19), 10526; https://doi.org/10.3390/ijms221910526 - 29 Sep 2021
Cited by 4 | Viewed by 1972
Abstract
RBM10 is an RNA-binding protein that regulates alternative splicing (AS). It localizes to the extra-nucleolar nucleoplasm and S1-1 nuclear bodies (NBs) in the nucleus. We investigated the biological significance of this localization in relation to its molecular function. Our analyses, employing deletion mutants, [...] Read more.
RBM10 is an RNA-binding protein that regulates alternative splicing (AS). It localizes to the extra-nucleolar nucleoplasm and S1-1 nuclear bodies (NBs) in the nucleus. We investigated the biological significance of this localization in relation to its molecular function. Our analyses, employing deletion mutants, revealed that RBM10 possesses two S1-1 NB-targeting sequences (NBTSs), one in the KEKE motif region and another in the C2H2 Zn finger (ZnF). These NBTSs act synergistically to localize RBM10 to S1-1 NBs. The C2H2 ZnF not only acts as an NBTS, but is also essential for AS regulation by RBM10. Moreover, RBM10 does not participate in S1-1 NB formation, and without alterations of RBM10 protein levels, its NB-localization changes, increasing as cellular transcriptional activity declines, and vice versa. These results indicate that RBM10 is a transient component of S1-1 NBs and is sequestered in NBs via its NBTSs when cellular transcription decreases. We propose that the C2H2 ZnF exerts its NB-targeting activity when RBM10 is unbound by pre-mRNAs, and that NB-localization of RBM10 is a mechanism to control its AS activity in the nucleus. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Pre-mRNA Splicing)
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18 pages, 3437 KiB  
Article
Identification of Nrl1 Domains Responsible for Interactions with RNA-Processing Factors and Regulation of Nrl1 Function by Phosphorylation
by Barbora Mikolaskova, Matus Jurcik, Ingrid Cipakova, Tomas Selicky, Jan Jurcik, Silvia Bagelova Polakova, Erika Stupenova, Andrej Dudas, Barbara Sivakova, Jana Bellova, Peter Barath, Lucia Aronica, Juraj Gregan and Lubos Cipak
Int. J. Mol. Sci. 2021, 22(13), 7011; https://doi.org/10.3390/ijms22137011 - 29 Jun 2021
Cited by 3 | Viewed by 2563
Abstract
Pre-mRNA splicing is a key process in the regulation of gene expression. In the fission yeast Schizosaccharomyces pombe, Nrl1 regulates splicing and expression of several genes and non-coding RNAs, and also suppresses the accumulation of R-loops. Here, we report analysis of interactions [...] Read more.
Pre-mRNA splicing is a key process in the regulation of gene expression. In the fission yeast Schizosaccharomyces pombe, Nrl1 regulates splicing and expression of several genes and non-coding RNAs, and also suppresses the accumulation of R-loops. Here, we report analysis of interactions between Nrl1 and selected RNA-processing proteins and regulation of Nrl1 function by phosphorylation. Bacterial two-hybrid system (BACTH) assays revealed that the N-terminal region of Nrl1 is important for the interaction with ATP-dependent RNA helicase Mtl1 while the C-terminal region of Nrl1 is important for interactions with spliceosome components Ctr1, Ntr2, and Syf3. Consistent with this result, tandem affinity purification showed that Mtl1, but not Ctr1, Ntr2, or Syf3, co-purifies with the N-terminal region of Nrl1. Interestingly, mass-spectrometry analysis revealed that in addition to previously identified phosphorylation sites, Nrl1 is also phosphorylated on serines 86 and 112, and that Nrl1-TAP co-purifies with Cka1, the catalytic subunit of casein kinase 2. In vitro assay showed that Cka1 can phosphorylate bacterially expressed Nrl1 fragments. An analysis of non-phosphorylatable nrl1 mutants revealed defects in gene expression and splicing consistent with the notion that phosphorylation is an important regulator of Nrl1 function. Taken together, our results provide insights into two mechanisms that are involved in the regulation of the spliceosome-associated factor Nrl1, namely domain-specific interactions between Nrl1 and RNA-processing proteins and post-translational modification of Nrl1 by phosphorylation. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Pre-mRNA Splicing)
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10 pages, 3501 KiB  
Communication
The Exon Junction Complex Core Represses Cancer-Specific Mature mRNA Re-splicing: A Potential Key Role in Terminating Splicing
by Yuta Otani, Ken-ichi Fujita, Toshiki Kameyama and Akila Mayeda
Int. J. Mol. Sci. 2021, 22(12), 6519; https://doi.org/10.3390/ijms22126519 - 17 Jun 2021
Cited by 7 | Viewed by 2963
Abstract
Using TSG101 pre-mRNA, we previously discovered cancer-specific re-splicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal [...] Read more.
Using TSG101 pre-mRNA, we previously discovered cancer-specific re-splicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal cells. We thus postulated that mRNA re-splicing is controlled by specific repressors, and we searched for repressor candidates by siRNA-based screening for mRNA re-splicing activity. We found that knock-down of EIF4A3, which is a core component of the exon junction complex (EJC), significantly promoted mRNA re-splicing. Remarkably, we could recapitulate cancer-specific mRNA re-splicing in normal cells by knock-down of any of the core EJC proteins, EIF4A3, MAGOH, or RBM8A (Y14), implicating the EJC core as the repressor of mRNA re-splicing often observed in cancer cells. We propose that the EJC core is a critical mRNA quality control factor to prevent over-splicing of mature mRNA. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Pre-mRNA Splicing)
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Review

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20 pages, 1557 KiB  
Review
Principles and Practical Considerations for the Analysis of Disease-Associated Alternative Splicing Events Using the Gateway Cloning-Based Minigene Vectors pDESTsplice and pSpliceExpress
by Elena Putscher, Michael Hecker, Brit Fitzner, Peter Lorenz and Uwe Klaus Zettl
Int. J. Mol. Sci. 2021, 22(10), 5154; https://doi.org/10.3390/ijms22105154 - 13 May 2021
Cited by 8 | Viewed by 3292
Abstract
Splicing is an important RNA processing step. Genetic variations can alter the splicing process and thereby contribute to the development of various diseases. Alterations of the splicing pattern can be examined by gene expression analyses, by computational tools for predicting the effects of [...] Read more.
Splicing is an important RNA processing step. Genetic variations can alter the splicing process and thereby contribute to the development of various diseases. Alterations of the splicing pattern can be examined by gene expression analyses, by computational tools for predicting the effects of genetic variants on splicing, and by splicing reporter minigene assays for studying alternative splicing events under defined conditions. The minigene assay is based on transient transfection of cells with a vector containing a genomic region of interest cloned between two constitutive exons. Cloning can be accomplished by the use of restriction enzymes or by site-specific recombination using Gateway cloning. The vectors pDESTsplice and pSpliceExpress represent two minigene systems based on Gateway cloning, which are available through the Addgene plasmid repository. In this review, we describe the features of these two splicing reporter minigene systems. Moreover, we provide an overview of studies in which determinants of alternative splicing were investigated by using pDESTsplice or pSpliceExpress. The studies were reviewed with regard to the investigated splicing regulatory events and the experimental strategy to construct and perform a splicing reporter minigene assay. We further elaborate on how analyses on the regulation of RNA splicing offer promising prospects for gaining important insights into disease mechanisms. Full article
(This article belongs to the Special Issue Mechanism and Regulation of Pre-mRNA Splicing)
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