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Special Issue "Pre-mRNA Splicing"

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

Deadline for manuscript submissions: closed (20 December 2014)

Special Issue Editor

Guest Editor
Prof. Akila Mayeda (Website)

Division of Gene Expression Mechanism, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan
Interests: pre-mRNA splicing; mechanism of splicing; regulation of splicing; aberrant splicing in diseases

Special Issue Information

Dear Colleagues,

In eukaryotes, most gene transcripts (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 the templates of proteins.  The higher eukaryotes have been evolved to gain more and more introns of increasing size; this evolution enables complexity and flexibility in the splicing process, and produces alternative splicing.  In humans, alternative splicing is a successful, major strategy for expressing a full proteome of at least 120,000 proteins from an unexpectedly small genome of, at most, 20,500 genes.  Recent studies have revealed that over 90% of human genes undergo alternative splicing; over 60% of such splicing processes are tissue-specifically regulated.  Regulations in the splicing process are definitely 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, which often leads to severe clinical consequences.

This special issue of the International Journal of Molecular Sciences (IJMS), “Pre-mRNA Splicing,” will cover a broad range of basic and applied studies of pre-mRNA splicing. Topics include, but are not limited to: the mechanism and regulation of constitutive and alternative splicing, pre-mRNA–protein interactions, hnRNP/mRNP assembly and functions, global analyses and evolutional studies of pre-mRNAs and splicing factors, and pre-mRNA processing in development and diseases.

Prof. Akila Mayeda
Guest Editor

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a 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 monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs).


Keywords

  • constitutive splicing
  • alternative splicing
  • aberrant splicing
  • splicing mechanism
  • splicing regulation
  • splicing factors
  • splicing enhancers
  • splicing silencers
  • snRNPs
  • hnRNPs
  • mRNPs
  • SR proteins

Published Papers (16 papers)

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Research

Jump to: Review

Open AccessArticle Accurate Splicing of HDAC6 Pre-mRNA Requires SON
Int. J. Mol. Sci. 2015, 16(3), 5886-5899; doi:10.3390/ijms16035886
Received: 18 December 2014 / Revised: 19 February 2015 / Accepted: 3 March 2015 / Published: 13 March 2015
PDF Full-text (933 KB) | HTML Full-text | XML Full-text
Abstract
Pre-mRNA splicing requires proper splice site selection mediated by many factors including snRNPs and serine-arginine rich (SR) splicing factors. Our lab previously reported that the SR-like protein SON maintains organization of pre-mRNA splicing factors in nuclear speckles as well as splicing of [...] Read more.
Pre-mRNA splicing requires proper splice site selection mediated by many factors including snRNPs and serine-arginine rich (SR) splicing factors. Our lab previously reported that the SR-like protein SON maintains organization of pre-mRNA splicing factors in nuclear speckles as well as splicing of many human transcripts including mRNAs coding for the chromatin-modifying enzymes HDAC6, ADA and SETD8. However, the mechanism by which SON maintains accurate splicing is unknown. To build tools for understanding SON-dependent pre-mRNA splicing, we constructed a minigene reporter plasmid driving expression of the genomic sequence spanning exons 26 through 29 of HDAC6. Following SON depletion, we observed altered splicing of HDAC6 reporter transcripts that showed exclusion of exons 27 and 28, reflecting the splicing patterns of endogenous HDAC6 mRNA. Importantly, loss of HDAC6 biological function was also observed, as indicated by truncated HDAC6 protein and corresponding absence of aggresome assembly activities of HDAC6 binding-of-ubiquitin zinc finger (BUZ) domain. We therefore propose that SON-mediated splicing regulation of HDAC6 is essential for supporting protein degradation pathways that prevent human disease. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessArticle Identification of the Specific Interactors of the Human Lariat RNA Debranching Enzyme 1 Protein
Int. J. Mol. Sci. 2015, 16(2), 3705-3721; doi:10.3390/ijms16023705
Received: 10 December 2014 / Accepted: 4 February 2015 / Published: 9 February 2015
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Abstract
In eukaryotes, pre-mRNA splicing is an essential step for gene expression. We have been analyzing post-splicing intron turnover steps in higher eukaryotes. Here, we report protein interaction between human Debranching enzyme 1 (hDbr1) and several factors found in the Intron Large (IL) [...] Read more.
In eukaryotes, pre-mRNA splicing is an essential step for gene expression. We have been analyzing post-splicing intron turnover steps in higher eukaryotes. Here, we report protein interaction between human Debranching enzyme 1 (hDbr1) and several factors found in the Intron Large (IL) complex, which is an intermediate complex of the intron degradation pathway. The hDbr1 protein specifically interacts with xeroderma pigmentosum, complementeation group A (XPA)-binding protein 2 (Xab2). We also attempted to identify specific interactors of hDbr1. Co-immunoprecipitation experiments followed by mass spectrometry analysis identified a novel protein as one of the specific interactors of hDbr1. This protein is well conserved among many species and shows the highest similarity to yeast Drn1, so it is designated as human Dbr1 associated ribonuclease 1 (hDrn1). hDrn1 directly interacts with hDbr1 through protein–protein interaction. Furthermore, hDrn1 shuttles between the nucleus and the cytoplasm, as hDbr1 protein does. These findings suggest that hDrn1 has roles in both the nucleus and the cytoplasm, which are highly likely to involve hDbr1. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessArticle Novel Transcription Factor Variants through RNA-Sequencing: The Importance of Being “Alternative”
Int. J. Mol. Sci. 2015, 16(1), 1755-1771; doi:10.3390/ijms16011755
Received: 3 November 2014 / Accepted: 26 December 2014 / Published: 13 January 2015
PDF Full-text (6491 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Alternative splicing is a pervasive mechanism of RNA maturation in higher eukaryotes, which increases proteomic diversity and biological complexity. It has a key regulatory role in several physiological and pathological states. The diffusion of Next Generation Sequencing, particularly of RNA-Sequencing, has exponentially [...] Read more.
Alternative splicing is a pervasive mechanism of RNA maturation in higher eukaryotes, which increases proteomic diversity and biological complexity. It has a key regulatory role in several physiological and pathological states. The diffusion of Next Generation Sequencing, particularly of RNA-Sequencing, has exponentially empowered the identification of novel transcripts revealing that more than 95% of human genes undergo alternative splicing. The highest rate of alternative splicing occurs in transcription factors encoding genes, mostly in Krüppel-associated box domains of zinc finger proteins. Since these molecules are responsible for gene expression, alternative splicing is a crucial mechanism to “regulate the regulators”. Indeed, different transcription factors isoforms may have different or even opposite functions. In this work, through a targeted re-analysis of our previously published RNA-Sequencing datasets, we identified nine novel transcripts in seven transcription factors genes. In silico analysis, combined with RT-PCR, cloning and Sanger sequencing, allowed us to experimentally validate these new variants. Through computational approaches we also predicted their novel structural and functional properties. Our findings indicate that alternative splicing is a major determinant of transcription factor diversity, confirming that accurate analysis of RNA-Sequencing data can reliably lead to the identification of novel transcripts, with potentially new functions. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessArticle Trans-Splicing Improvement by the Combined Application of Antisense Strategies
Int. J. Mol. Sci. 2015, 16(1), 1179-1191; doi:10.3390/ijms16011179
Received: 21 November 2014 / Accepted: 25 December 2014 / Published: 6 January 2015
Cited by 4 | PDF Full-text (1540 KB) | HTML Full-text | XML Full-text
Abstract
Spliceosome-mediated RNA trans-splicing has become an emergent tool for the repair of mutated pre-mRNAs in the treatment of genetic diseases. RNA trans-splicing molecules (RTMs) are designed to induce a specific trans-splicing reaction via a binding domain for a respective [...] Read more.
Spliceosome-mediated RNA trans-splicing has become an emergent tool for the repair of mutated pre-mRNAs in the treatment of genetic diseases. RNA trans-splicing molecules (RTMs) are designed to induce a specific trans-splicing reaction via a binding domain for a respective target pre-mRNA region. A previously established reporter-based screening system allows us to analyze the impact of various factors on the RTM trans-splicing efficiency in vitro. Using this system, we are further able to investigate the potential of antisense RNAs (AS RNAs), presuming to improve the trans-splicing efficiency of a selected RTM, specific for intron 102 of COL7A1. Mutations in the COL7A1 gene underlie the dystrophic subtype of the skin blistering disease epidermolysis bullosa (DEB). We have shown that co-transfections of the RTM and a selected AS RNA, interfering with competitive splicing elements on a COL7A1-minigene (COL7A1-MG), lead to a significant increase of the RNA trans-splicing efficiency. Thereby, accurate trans-splicing between the RTM and the COL7A1-MG is represented by the restoration of full-length green fluorescent protein GFP on mRNA and protein level. This mechanism can be crucial for the improvement of an RTM-mediated correction, especially in cases where a high trans-splicing efficiency is required. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessArticle Abscisic Acid (ABA) Regulation of Arabidopsis SR Protein Gene Expression
Int. J. Mol. Sci. 2014, 15(10), 17541-17564; doi:10.3390/ijms151017541
Received: 2 August 2014 / Revised: 13 September 2014 / Accepted: 23 September 2014 / Published: 29 September 2014
Cited by 5 | PDF Full-text (642 KB) | HTML Full-text | XML Full-text
Abstract
Serine/arginine-rich (SR) proteins are major modulators of alternative splicing, a key generator of proteomic diversity and flexible means of regulating gene expression likely to be crucial in plant environmental responses. Indeed, mounting evidence implicates splicing factors in signal transduction of the abscisic [...] Read more.
Serine/arginine-rich (SR) proteins are major modulators of alternative splicing, a key generator of proteomic diversity and flexible means of regulating gene expression likely to be crucial in plant environmental responses. Indeed, mounting evidence implicates splicing factors in signal transduction of the abscisic acid (ABA) phytohormone, which plays pivotal roles in the response to various abiotic stresses. Using real-time RT-qPCR, we analyzed total steady-state transcript levels of the 18 SR and two SR-like genes from Arabidopsis thaliana in seedlings treated with ABA and in genetic backgrounds with altered expression of the ABA-biosynthesis ABA2 and the ABA-signaling ABI1 and ABI4 genes. We also searched for ABA-responsive cis elements in the upstream regions of the 20 genes. We found that members of the plant-specific SC35-Like (SCL) Arabidopsis SR protein subfamily are distinctively responsive to exogenous ABA, while the expression of seven SR and SR-related genes is affected by alterations in key components of the ABA pathway. Finally, despite pervasiveness of established ABA-responsive promoter elements in Arabidopsis SR and SR-like genes, their expression is likely governed by additional, yet unidentified cis-acting elements. Overall, this study pinpoints SR34, SR34b, SCL30a, SCL28, SCL33, RS40, SR45 and SR45a as promising candidates for involvement in ABA-mediated stress responses. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessArticle BRCA1 Exon 11, a CERES (Composite Regulatory Element of Splicing) Element Involved in Splice Regulation
Int. J. Mol. Sci. 2014, 15(7), 13045-13059; doi:10.3390/ijms150713045
Received: 13 April 2014 / Revised: 17 June 2014 / Accepted: 4 July 2014 / Published: 23 July 2014
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Abstract
Unclassified variants (UV) of BRCA1 can affect normal pre-mRNA splicing. Here, we investigate the UV c.693G>A, a “silent” change in BRCA1 exon 11, which we have found induces aberrant splicing in patient carriers and in vitro. Using a minigene assay, we [...] Read more.
Unclassified variants (UV) of BRCA1 can affect normal pre-mRNA splicing. Here, we investigate the UV c.693G>A, a “silent” change in BRCA1 exon 11, which we have found induces aberrant splicing in patient carriers and in vitro. Using a minigene assay, we show that the UV c.693G>A has a strong effect on the splicing isoform ratio of BRCA1. Systematic site-directed mutagenesis of the area surrounding the nucleotide position c.693G>A induced variable changes in the level of exon 11 inclusion/exclusion in the mRNA, pointing to the presence of a complex regulatory element with overlapping enhancer and silencer functions. Accordingly, protein binding analysis in the region detected several splicing regulatory factors involved, including SRSF1, SRSF6 and SRSF9, suggesting that this sequence represents a composite regulatory element of splicing (CERES). Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessArticle Supraspliceosomes at Defined Functional States Portray the Pre-Assembled Nature of the Pre-mRNA Processing Machine in the Cell Nucleus
Int. J. Mol. Sci. 2014, 15(7), 11637-11664; doi:10.3390/ijms150711637
Received: 10 April 2014 / Revised: 5 June 2014 / Accepted: 18 June 2014 / Published: 30 June 2014
Cited by 3 | PDF Full-text (2835 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
When isolated from mammalian cell nuclei, all nuclear pre-mRNAs are packaged in multi-subunit large ribonucleoprotein complexes—supraspliceosomes—composed of four native spliceosomes interconnected by the pre-mRNA. Supraspliceosomes contain all five spliceosomal U snRNPs, together with other splicing factors, and are functional in splicing. Supraspliceosomes [...] Read more.
When isolated from mammalian cell nuclei, all nuclear pre-mRNAs are packaged in multi-subunit large ribonucleoprotein complexes—supraspliceosomes—composed of four native spliceosomes interconnected by the pre-mRNA. Supraspliceosomes contain all five spliceosomal U snRNPs, together with other splicing factors, and are functional in splicing. Supraspliceosomes studied thus far represent the steady-state population of nuclear pre-mRNAs that were isolated at different stages of the splicing reaction. To analyze specific splicing complexes, here, we affinity purified Pseudomonas aeruginosa phage 7 (PP7)-tagged splicing complexes assembled in vivo on Adenovirus Major Late (AdML) transcripts at specific functional stages, and characterized them using molecular techniques including mass spectrometry. First, we show that these affinity purified splicing complexes assembled on PP7-tagged AdML mRNA or on PP7-tagged AdML pre-mRNA are assembled in supraspliceosomes. Second, similar to the general population of supraspliceosomes, these defined supraspliceosomes populations are assembled with all five U snRNPs at all splicing stages. This study shows that dynamic changes in base-pairing interactions of U snRNA:U snRNA and U snRNA:pre-mRNA that occur in vivo during the splicing reaction do not require changes in U snRNP composition of the supraspliceosome. Furthermore, there is no need to reassemble a native spliceosome for the splicing of each intron, and rearrangements of the interactions will suffice. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessArticle Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome
Int. J. Mol. Sci. 2014, 15(6), 10350-10364; doi:10.3390/ijms150610350
Received: 9 April 2014 / Revised: 12 May 2014 / Accepted: 20 May 2014 / Published: 10 June 2014
Cited by 3 | PDF Full-text (919 KB) | HTML Full-text | XML Full-text
Abstract
Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by distinctive craniofacial features, growth retardation, cognitive impairment, limb defects, hirsutism, and multisystem involvement. Mutations in five genes encoding structural components (SMC1A, SMC3, RAD21) or functionally associated [...] Read more.
Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by distinctive craniofacial features, growth retardation, cognitive impairment, limb defects, hirsutism, and multisystem involvement. Mutations in five genes encoding structural components (SMC1A, SMC3, RAD21) or functionally associated factors (NIPBL, HDAC8) of the cohesin complex have been found in patients with CdLS. In about 60% of the patients, mutations in NIPBL could be identified. Interestingly, 17% of them are predicted to change normal splicing, however, detailed molecular investigations are often missing. Here, we report the first systematic study of the physiological splicing of the NIPBL gene, that would reveal the identification of four new splicing isoforms ΔE10, ΔE12, ΔE33,34, and B’. Furthermore, we have investigated nine mutations affecting splice-sites in the NIPBL gene identified in twelve CdLS patients. All mutations have been examined on the DNA and RNA level, as well as by in silico analyses. Although patients with mutations affecting NIPBL splicing show a broad clinical variability, the more severe phenotypes seem to be associated with aberrant transcripts resulting in a shift of the reading frame. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessArticle Effects of RNAi-Mediated Knockdown of Histone Methyltransferases on the Sex-Specific mRNA Expression of Imp in the Silkworm Bombyx mori
Int. J. Mol. Sci. 2014, 15(4), 6772-6796; doi:10.3390/ijms15046772
Received: 19 February 2014 / Revised: 25 March 2014 / Accepted: 10 April 2014 / Published: 22 April 2014
Cited by 3 | PDF Full-text (4844 KB) | HTML Full-text | XML Full-text
Abstract
Sexual differentiation in Bombyx mori is controlled by sex-specific splicing of Bmdsx, which results in the omission of exons 3 and 4 in a male-specific manner. In B. mori, insulin-like growth factor II mRNA-binding protein (Imp) is a male-specific factor [...] Read more.
Sexual differentiation in Bombyx mori is controlled by sex-specific splicing of Bmdsx, which results in the omission of exons 3 and 4 in a male-specific manner. In B. mori, insulin-like growth factor II mRNA-binding protein (Imp) is a male-specific factor involved in male-specific splicing of Bmdsx. Male-specific Imp mRNA results from the male-specific inclusion of exon 8. To verify the link between histone methylation and alternative RNA processing in Imp, we examined the effects of RNAi-mediated knockdown of several histone methyltransferases on the sex-specific mRNA expression of Imp. As a result, male-specific expression of Imp mRNA was completely abolished when expression of the H3K79 methyltransferase DOT1L was repressed to <10% of that in control males. Chromatin immunoprecipitation-quantitative PCR analysis revealed a higher distribution of H3K79me2 in normal males than in normal females across Imp. RNA polymerase II (RNAP II) processivity assays indicated that RNAi knockdown of DOT1L in males caused a twofold decrease in RNAP II processivity compared to that in control males, with almost equivalent levels to those observed in normal females. Inhibition of RNAP II-mediated elongation in male cells repressed the male-specific splicing of Imp. Our data suggest the possibility that H3K79me2 accumulation along Imp is associated with the male-specific alternative processing of Imp mRNA that results from increased RNAP II processivity. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessArticle HuR and TIA1/TIAL1 Are Involved in Regulation of Alternative Splicing of SIRT1 Pre-mRNA
Int. J. Mol. Sci. 2014, 15(2), 2946-2958; doi:10.3390/ijms15022946
Received: 19 November 2013 / Revised: 19 January 2014 / Accepted: 10 February 2014 / Published: 20 February 2014
Cited by 2 | PDF Full-text (597 KB) | HTML Full-text | XML Full-text
Abstract
SIRT1 is a pleiotropic protein that plays critical and multifunctional roles in metabolism, senescence, longevity, stress-responses, and cancer, and has become an important therapeutic target across a range of diseases. Recent research demonstrated that SIRT1 pre-mRNA undergoes alternative splicing to produce different [...] Read more.
SIRT1 is a pleiotropic protein that plays critical and multifunctional roles in metabolism, senescence, longevity, stress-responses, and cancer, and has become an important therapeutic target across a range of diseases. Recent research demonstrated that SIRT1 pre-mRNA undergoes alternative splicing to produce different isoforms, such as SIRT1 full-length and SIRT1-∆Exon8 variants. Previous studies revealed these SIRT1 mRNA splice variants convey different characteristics and functions to the protein, which may in turn explain the multifunctional roles of SIRT1. However, the mechanisms underlying the regulation of SIRT1 alternative splicing remain to be elucidated. Our objective is to search for new pathways that regulate of SIRT1 alternative splicing. Here we describe experiments showing that HuR and TIA1/TIAL1, two kinds of RNA-binding proteins, were involved in the regulation of alternative splicing of SIRT1 pre-mRNA under normal and stress circumstances: HuR increased SIRT1-∆Exon8 by promoting SIRT1 exon 8 exclusion, whereas TIA1/TIAL1 inhibition of the exon 8 exclusion led to a decrease in SIRT1-∆Exon8 mRNA levels. This study provides novel insight into how the alternative splicing of SIRT1 pre-mRNA is regulated, which has fundamental implications for understanding the critical and multifunctional roles of SIRT1. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)

Review

Jump to: Research

Open AccessReview Mammalian Introns: When the Junk Generates Molecular Diversity
Int. J. Mol. Sci. 2015, 16(3), 4429-4452; doi:10.3390/ijms16034429
Received: 16 December 2014 / Revised: 6 February 2015 / Accepted: 11 February 2015 / Published: 20 February 2015
Cited by 4 | PDF Full-text (3703 KB) | HTML Full-text | XML Full-text
Abstract
Introns represent almost half of the human genome, yet their vast majority is eliminated from eukaryotic transcripts through RNA splicing. Nevertheless, they feature key elements and functions that deserve further interest. At the level of DNA, introns are genomic segments that can [...] Read more.
Introns represent almost half of the human genome, yet their vast majority is eliminated from eukaryotic transcripts through RNA splicing. Nevertheless, they feature key elements and functions that deserve further interest. At the level of DNA, introns are genomic segments that can shelter independent transcription units for coding and non-coding RNAs which transcription may interfere with that of the host gene, and regulatory elements that can influence gene expression and splicing itself. From the RNA perspective, some introns can be subjected to alternative splicing. Intron retention appear to provide some plasticity to the nature of the protein produced, its distribution in a given cell type and timing of its translation. Intron retention may also serve as a switch to produce coding or non-coding RNAs from the same transcription unit. Conversely, splicing of introns has been directly implicated in the production of small regulatory RNAs. Hence, splicing of introns also appears to provide plasticity to the type of RNA produced from a genetic locus (coding, non-coding, short or long). We addressed these aspects to add to our understanding of mechanisms that control the fate of introns and could be instrumental in regulating genomic output and hence cell fate. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessReview Regulation of Translation Factor EEF1D Gene Function by Alternative Splicing
Int. J. Mol. Sci. 2015, 16(2), 3970-3979; doi:10.3390/ijms16023970
Received: 19 December 2014 / Accepted: 4 February 2015 / Published: 12 February 2015
Cited by 2 | PDF Full-text (930 KB) | HTML Full-text | XML Full-text
Abstract
Alternative splicing is an exquisite mechanism that allows one coding gene to have multiple functions. The alternative splicing machinery is necessary for proper development, differentiation and stress responses in a variety of organisms, and disruption of this machinery is often implicated in [...] Read more.
Alternative splicing is an exquisite mechanism that allows one coding gene to have multiple functions. The alternative splicing machinery is necessary for proper development, differentiation and stress responses in a variety of organisms, and disruption of this machinery is often implicated in human diseases. Previously, we discovered a long form of eukaryotic elongation factor 1Bδ (eEF1Bδ; this long-form eEF1Bδ results from alternative splicing of EEF1D transcripts and regulates the cellular stress response by transcriptional activation, not translational enhancement, of heat-shock responsive genes. In this review, we discuss the molecular function of EEF1D alternative splicing products and the estimated implication of human diseases. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
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Open AccessReview Regulation of Human Adenovirus Alternative RNA Splicing by the Adenoviral L4-33K and L4-22K Proteins
Int. J. Mol. Sci. 2015, 16(2), 2893-2912; doi:10.3390/ijms16022893
Received: 22 December 2014 / Revised: 6 January 2015 / Accepted: 22 January 2015 / Published: 28 January 2015
Cited by 1 | PDF Full-text (1978 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Adenovirus makes extensive use of alternative RNA splicing to produce a complex set of spliced viral mRNAs. Studies aimed at characterizing the interactions between the virus and the host cell RNA splicing machinery have identified three viral proteins of special significance for [...] Read more.
Adenovirus makes extensive use of alternative RNA splicing to produce a complex set of spliced viral mRNAs. Studies aimed at characterizing the interactions between the virus and the host cell RNA splicing machinery have identified three viral proteins of special significance for the control of late viral gene expression: L4-33K, L4-22K, and E4-ORF4. L4-33K is a viral alternative RNA splicing factor that controls L1 alternative splicing via an interaction with the cellular protein kinases Protein Kinase A (PKA) and DNA-dependent protein kinase (DNA-PK). L4-22K is a viral transcription factor that also has been implicated in the splicing of a subset of late viral mRNAs. E4-ORF4 is a viral protein that binds the cellular protein phosphatase IIA (PP2A) and controls Serine/Arginine (SR)-rich protein activity by inducing SR protein dephosphorylation. The L4-33K, and most likely also the L4-22K protein, are highly phosphorylated in vivo. Here we will review the function of these viral proteins in the post-transcriptional control of adenoviral gene expression and further discuss the significance of potential protein kinases phosphorylating the L4-33K and/or L4-22K proteins. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessReview Alternative RNA Structure-Coupled Gene Regulations in Tumorigenesis
Int. J. Mol. Sci. 2015, 16(1), 452-475; doi:10.3390/ijms16010452
Received: 31 October 2014 / Accepted: 16 December 2014 / Published: 29 December 2014
PDF Full-text (631 KB) | HTML Full-text | XML Full-text
Abstract
Alternative RNA structures (ARSs), or alternative transcript isoforms, are critical for regulating cellular phenotypes in humans. In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs) and intronic regions, [...] Read more.
Alternative RNA structures (ARSs), or alternative transcript isoforms, are critical for regulating cellular phenotypes in humans. In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs) and intronic regions, thus also affecting the regulatory effects of these regions. ARS may introduce premature stop codon(s) into a transcript, and render the transcript susceptible to nonsense-mediated decay, which in turn can influence the overall gene expression level. Meanwhile, ARS can regulate the presence/absence of upstream open reading frames and microRNA targeting sites in 5'UTRs and 3'UTRs, respectively, thus affecting translational efficiencies and protein expression levels. Furthermore, since ARS may alter exon-intron structures, it can influence the biogenesis of intronic microRNAs and indirectly affect the expression of the target genes of these microRNAs. The connections between ARS and multiple regulatory mechanisms underline the importance of ARS in determining cell fate. Accumulating evidence indicates that ARS-coupled regulations play important roles in tumorigenesis. Here I will review our current knowledge in this field, and discuss potential future directions. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessReview Alternative Splicing in Plant Immunity
Int. J. Mol. Sci. 2014, 15(6), 10424-10445; doi:10.3390/ijms150610424
Received: 14 April 2014 / Revised: 12 May 2014 / Accepted: 14 May 2014 / Published: 10 June 2014
Cited by 11 | PDF Full-text (727 KB) | HTML Full-text | XML Full-text
Abstract
Alternative splicing (AS) occurs widely in plants and can provide the main source of transcriptome and proteome diversity in an organism. AS functions in a range of physiological processes, including plant disease resistance, but its biological roles and functional mechanisms remain poorly [...] Read more.
Alternative splicing (AS) occurs widely in plants and can provide the main source of transcriptome and proteome diversity in an organism. AS functions in a range of physiological processes, including plant disease resistance, but its biological roles and functional mechanisms remain poorly understood. Many plant disease resistance (R) genes undergo AS, and several R genes require alternatively spliced transcripts to produce R proteins that can specifically recognize pathogen invasion. In the finely-tuned process of R protein activation, the truncated isoforms generated by AS may participate in plant disease resistance either by suppressing the negative regulation of initiation of immunity, or by directly engaging in effector-triggered signaling. Although emerging research has shown the functional significance of AS in plant biotic stress responses, many aspects of this topic remain to be understood. Several interesting issues surrounding the AS of R genes, especially regarding its functional roles and regulation, will require innovative techniques and additional research to unravel. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
Open AccessReview A View of Pre-mRNA Splicing from RNase R Resistant RNAs
Int. J. Mol. Sci. 2014, 15(6), 9331-9342; doi:10.3390/ijms15069331
Received: 8 April 2014 / Revised: 8 May 2014 / Accepted: 16 May 2014 / Published: 26 May 2014
Cited by 11 | PDF Full-text (918 KB) | HTML Full-text | XML Full-text
Abstract
During pre-mRNA splicing, exons in the primary transcript are precisely connected to generate an mRNA. Intron lariat RNAs are formed as by-products of this process. In addition, some exonic circular RNAs (circRNAs) may also result from exon skipping as by-products. Lariat RNAs [...] Read more.
During pre-mRNA splicing, exons in the primary transcript are precisely connected to generate an mRNA. Intron lariat RNAs are formed as by-products of this process. In addition, some exonic circular RNAs (circRNAs) may also result from exon skipping as by-products. Lariat RNAs and circRNAs are both RNase R resistant RNAs. RNase R is a strong 3' to 5' exoribonuclease, which efficiently degrades linear RNAs, such as mRNAs and rRNAs; therefore, the circular parts of lariat RNAs and the circRNAs can be segregated from eukaryotic total RNAs by their RNase R resistance. Thus, RNase R resistant RNAs could provide unexplored splicing information not available from mRNAs. Analyses of these RNAs identified repeating splicing phenomena, such as re-splicing of mature mRNAs and nested splicing. Moreover, circRNA might function as microRNA sponges. There is an enormous variety of endogenous circRNAs, which are generally synthesized in cells and tissues. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing)
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