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Pre-mRNA Splicing 2016
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Pre-mRNA Splicing 2016

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

Deadline for manuscript submissions: closed (31 December 2016) | Viewed by 106196

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 (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
  • pre-mRNA processing in development and diseases

Prof. Akila Mayeda
Guest Editor

Manuscript Submission Information

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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.

Keywords

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

Published Papers (15 papers)

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Research

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1499 KiB  
Article
The Characterization of GSDMB Splicing and Backsplicing Profiles Identifies Novel Isoforms and a Circular RNA That Are Dysregulated in Multiple Sclerosis
by Giulia Cardamone, Elvezia Maria Paraboschi, Valeria Rimoldi, Stefano Duga, Giulia Soldà and Rosanna Asselta
Int. J. Mol. Sci. 2017, 18(3), 576; https://doi.org/10.3390/ijms18030576 - 07 Mar 2017
Cited by 87 | Viewed by 7272
Abstract
Abnormalities in alternative splicing (AS) are emerging as recurrent features in autoimmune diseases (AIDs). In particular, a growing body of evidence suggests the existence of a pathogenic association between a generalized defect in splicing regulatory genes and multiple sclerosis (MS). Moreover, several studies [...] Read more.
Abnormalities in alternative splicing (AS) are emerging as recurrent features in autoimmune diseases (AIDs). In particular, a growing body of evidence suggests the existence of a pathogenic association between a generalized defect in splicing regulatory genes and multiple sclerosis (MS). Moreover, several studies have documented an unbalance in alternatively-spliced isoforms in MS patients possibly contributing to the disease etiology. In this work, using a combination of PCR-based techniques (reverse-transcription (RT)-PCR, fluorescent-competitive, real-time, and digital RT-PCR assays), we investigated the alternatively-spliced gene encoding Gasdermin B, GSDMB, which was repeatedly associated with susceptibility to asthma and AIDs. The in-depth characterization of GSDMB AS and backsplicing profiles led us to the identification of an exonic circular RNA (ecircRNA) as well as of novel GSDMB in-frame and out-of-frame isoforms. The non-productive splicing variants were shown to be downregulated by the nonsense-mediated mRNA decay (NMD) in human cell lines, suggesting that GSDMB levels are significantly modulated by NMD. Importantly, both AS isoforms and the identified ecircRNA were significantly dysregulated in peripheral blood mononuclear cells of relapsing-remitting MS patients compared to controls, further supporting the notion that aberrant RNA metabolism is a characteristic feature of the disease. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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3132 KiB  
Article
mRNA Quantification of NIPBL Isoforms A and B in Adult and Fetal Human Tissues, and a Potentially Pathological Variant Affecting Only Isoform A in Two Patients with Cornelia de Lange Syndrome
by Beatriz Puisac, María-Esperanza Teresa-Rodrigo, María Hernández-Marcos, Carolina Baquero-Montoya, María-Concepción Gil-Rodríguez, Torkild Visnes, Christopher Bot, Paulino Gómez-Puertas, Frank J. Kaiser, Feliciano J. Ramos, Lena Ström and Juan Pié
Int. J. Mol. Sci. 2017, 18(3), 481; https://doi.org/10.3390/ijms18030481 - 23 Feb 2017
Cited by 1 | Viewed by 4813
Abstract
Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by craniofacial dysmorphia, growth retardation, limb malformations, and intellectual disability. Approximately 60% of patients with CdLS carry a recognizable pathological variant in the NIPBL gene, of which two isoforms, A and B, [...] Read more.
Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by craniofacial dysmorphia, growth retardation, limb malformations, and intellectual disability. Approximately 60% of patients with CdLS carry a recognizable pathological variant in the NIPBL gene, of which two isoforms, A and B, have been identified, and which only differ in the C-terminal segment. In this work, we describe the distribution pattern of the isoforms A and B mRNAs in tissues of adult and fetal origin, by qPCR (quantitative polymerase chain reaction). Our results show a higher gene expression of the isoform A, even though both seem to have the same tissue distribution. Interestingly, the expression in fetal tissues is higher than that of adults, especially in brain and skeletal muscle. Curiously, the study of fibroblasts of two siblings with a mild CdLS phenotype and a pathological variant specific of the isoform A of NIPBL (c.8387A > G; P.Tyr2796Cys), showed a similar reduction in both isoforms, and a normal sensitivity to DNA damage. Overall, these results suggest that the position of the pathological variant at the 3´ end of the NIPBL gene affecting only isoform A, is likely to be the cause of the atypical mild phenotype of the two brothers. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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3544 KiB  
Article
Novel Nine-Exon AR Transcripts (Exon 1/Exon 1b/Exons 2–8) in Normal and Cancerous Breast and Prostate Cells
by Dong Gui Hu, Ross A. McKinnon, Julie-Ann Hulin, Peter I. Mackenzie and Robyn Meech
Int. J. Mol. Sci. 2017, 18(1), 40; https://doi.org/10.3390/ijms18010040 - 27 Dec 2016
Cited by 7 | Viewed by 7243
Abstract
Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants [...] Read more.
Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2–8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b. Moreover, we identified AR transcripts in both normal and cancerous breast and prostate cells that contained either exon 1b or 1b/TAG spliced between the canonical exon 1 and exon 2, generating nine-exon AR transcripts that we have named isoforms 3a and 3b. The proteins encoded by these new AR variants could regulate androgen-responsive reporters in breast and prostate cancer cells under androgen-depleted conditions. Analysis of type 3 AR-GFP fusion proteins showed partial nuclear localization in PC3 cells under androgen-depleted conditions, supporting androgen-independent activation of the AR. Type 3 AR proteins inhibited androgen-induced growth of LNCaP cells. Microarray analysis identified a small set of type 3a AR target genes in LNCaP cells, including genes known to modulate growth and proliferation of prostate cancer (PCGEM1, PEG3, EPHA3, and EFNB2) or other types of human cancers (TOX3, ST8SIA4, and SLITRK3), and genes that are diagnostic/prognostic biomarkers of prostate cancer (GRINA3, and BCHE). Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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8493 KiB  
Article
Functional Studies and In Silico Analyses to Evaluate Non-Coding Variants in Inherited Cardiomyopathies
by Giulia Frisso, Nicola Detta, Pamela Coppola, Cristina Mazzaccara, Maria Rosaria Pricolo, Antonio D’Onofrio, Giuseppe Limongelli, Raffaele Calabrò and Francesco Salvatore
Int. J. Mol. Sci. 2016, 17(11), 1883; https://doi.org/10.3390/ijms17111883 - 10 Nov 2016
Cited by 24 | Viewed by 4886
Abstract
Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis [...] Read more.
Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis of intronic variants can reveal their impact on the splicing process, but the consequence of a given substitution is generally not predictable. The aim of this study was to functionally test five intronic variants (MYBPC3-c.506-2A>C, MYBPC3-c.906-7G>T, MYBPC3-c.2308+3G>C, SCN5A-c.393-5C>A, and ACTC1-c.617-7T>C) found in five patients affected by inherited cardiomyopathies in the attempt to verify their pathogenic role. Analysis of the MYBPC3-c.506-2A>C mutation in mRNA from the peripheral blood of one of the patients affected by hypertrophic cardiac myopathy revealed the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (MYBPC3-G169AfsX14). In the other four patients, we generated minigene constructs and transfected them in HEK-293 cells. This minigene approach showed that MYBPC3-c.2308+3G>C and SCN5A-c.393-5C>A altered pre-mRNA processing, thus resulting in the skipping of one exon. No alterations were found in either MYBPC3-c.906-7G>T or ACTC1-c.617-7T>C. In conclusion, functional in vitro analysis of the effects of potential splicing mutations can confirm or otherwise the putative pathogenicity of non-coding mutations, and thus help to guide the patient's clinical management and improve genetic counseling in affected families. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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7856 KiB  
Article
Cloning and Expression of Ecdysone Receptor and Retinoid X Receptor from Procambarus clarkii: Induction by Eyestalk Ablation
by Tian-Hao Dai, Ali Sserwadda, Kun Song, Ya-Nan Zang and Huai-Shun Shen
Int. J. Mol. Sci. 2016, 17(10), 1739; https://doi.org/10.3390/ijms17101739 - 18 Oct 2016
Cited by 18 | Viewed by 4076
Abstract
Ecdysone receptor and retinoid X receptor are key regulators in molting. Here, full length ecdysone receptor (PcEcR) and retinoid X receptor (PcRXR) cDNAs from Procambarus clarkii were cloned. Full length cDNA of PcEcR has 2500 bp, encoding 576 amino [...] Read more.
Ecdysone receptor and retinoid X receptor are key regulators in molting. Here, full length ecdysone receptor (PcEcR) and retinoid X receptor (PcRXR) cDNAs from Procambarus clarkii were cloned. Full length cDNA of PcEcR has 2500 bp, encoding 576 amino acid proteins, and full length cDNA of PcRXR has 2593 bp, in which a 15 bp and a 204 bp insert/deletion splice variant regions in DNA binding domain and hinge domain were identified. The two splice variant regions in PcRXR result four isoforms: PcRXR1-4, encoding 525, 520, 457 and 452 amino acids respectively. PcEcR was highly expressed in the hepatopancreas and eyestalk and PcRXR was highly expressed in the eyestalk among eight examined tissues. Both PcEcR and PcRXR had induced expression after eyestalk ablation (ESA) in the three examined tissues. In muscle, PcEcR and PcRXR were upregulated after ESA, PcEcR reached the highest level on day 3 after ESA and increased 33.5-fold relative to day 0, and PcRXR reached highest the level on day 1 after ESA and increased 2.7-fold relative to day 0. In the hepatopancreas, PcEcR and PcRXR dEcReased continuously after ESA, and the expression levels of PcEcR and PcRXR were only 0.7% and 1.7% on day 7 after ESA relative to day 0, respectively. In the ovaries, PcEcR was upregulated after ESA, reached the highest level on day 3 after ESA, increased 3.0-fold relative to day 0, and the expression level of PcRXR changed insignificantly after ESA (p > 0.05). The different responses of PcEcR and PcRXR after ESA indicates that different tissues play different roles (and coordinates their functions) in molting. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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3551 KiB  
Article
Endogenous Multiple Exon Skipping and Back-Splicing at the DMD Mutation Hotspot
by Hitoshi Suzuki, Yoshitsugu Aoki, Toshiki Kameyama, Takashi Saito, Satoru Masuda, Jun Tanihata, Tetsuya Nagata, Akila Mayeda, Shin’ichi Takeda and Toshifumi Tsukahara
Int. J. Mol. Sci. 2016, 17(10), 1722; https://doi.org/10.3390/ijms17101722 - 13 Oct 2016
Cited by 36 | Viewed by 8339
Abstract
Duchenne muscular dystrophy (DMD) is a severe muscular disorder. It was reported that multiple exon skipping (MES), targeting exon 45–55 of the DMD gene, might improve patients’ symptoms because patients who have a genomic deletion of all these exons showed very mild symptoms. [...] Read more.
Duchenne muscular dystrophy (DMD) is a severe muscular disorder. It was reported that multiple exon skipping (MES), targeting exon 45–55 of the DMD gene, might improve patients’ symptoms because patients who have a genomic deletion of all these exons showed very mild symptoms. Thus, exon 45–55 skipping treatments for DMD have been proposed as a potential clinical cure. Herein, we detected the expression of endogenous exons 44–56 connected mRNA transcript of the DMD using total RNAs derived from human normal skeletal muscle by reverse transcription polymerase chain reaction (RT-PCR), and identified a total of eight types of MES products around the hotspot. Surprisingly, the 5′ splice sites of recently reported post-transcriptional introns (remaining introns after co-transcriptional splicing) act as splicing donor sites for MESs. We also tested exon combinations to generate DMD circular RNAs (circRNAs) and determined the preferential splice sites of back-splicing, which are involved not only in circRNA generation, but also in MESs. Our results fit the current circRNA-generation model, suggesting that upstream post-transcriptional introns trigger MES and generate circRNA because its existence is critical for the intra-intronic interaction or for extremely distal splicing. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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3831 KiB  
Article
Designing Efficient Double RNA trans-Splicing Molecules for Targeted RNA Repair
by Clemens Hüttner, Eva M. Murauer, Stefan Hainzl, Thomas Kocher, Anna Neumayer, Julia Reichelt, Johann W. Bauer and Ulrich Koller
Int. J. Mol. Sci. 2016, 17(10), 1609; https://doi.org/10.3390/ijms17101609 - 22 Sep 2016
Cited by 7 | Viewed by 5795
Abstract
RNA trans-splicing is a promising tool for mRNA modification in a diversity of genetic disorders. In particular, the substitution of internal exons of a gene by combining 3′ and 5′ RNA trans-splicing seems to be an elegant way to modify especially [...] Read more.
RNA trans-splicing is a promising tool for mRNA modification in a diversity of genetic disorders. In particular, the substitution of internal exons of a gene by combining 3′ and 5′ RNA trans-splicing seems to be an elegant way to modify especially large pre-mRNAs. Here we discuss a robust method for designing double RNA trans-splicing molecules (dRTM). We demonstrate how the technique can be implemented in an endogenous setting, using COL7A1, the gene encoding type VII collagen, as a target. An RTM screening system was developed with the aim of testing the replacement of two internal COL7A1 exons, harbouring a homozygous mutation, with the wild-type version. The most efficient RTMs from a pool of randomly generated variants were selected via our fluorescence-based screening system and adapted for use in an in vitro disease model system. Transduction of type VII collagen-deficient keratinocytes with the selected dRTM led to accurate replacement of two internal COL7A1 exons resulting in a restored wild-type RNA sequence. This is the first study demonstrating specific exon replacement by double RNA trans-splicing within an endogenous transcript in cultured cells, corroborating the utility of this technology for mRNA repair in a variety of genetic disorders. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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6668 KiB  
Article
The Exon Junction Complex Controls the Efficient and Faithful Splicing of a Subset of Transcripts Involved in Mitotic Cell-Cycle Progression
by Kazuhiro Fukumura, Shunichi Wakabayashi, Naoyuki Kataoka, Hiroshi Sakamoto, Yutaka Suzuki, Kenta Nakai, Akila Mayeda and Kunio Inoue
Int. J. Mol. Sci. 2016, 17(8), 1153; https://doi.org/10.3390/ijms17081153 - 02 Aug 2016
Cited by 24 | Viewed by 12500
Abstract
The exon junction complex (EJC) that is deposited onto spliced mRNAs upstream of exon–exon junctions plays important roles in multiple post-splicing gene expression events, such as mRNA export, surveillance, localization, and translation. However, a direct role for the human EJC in pre-mRNA splicing [...] Read more.
The exon junction complex (EJC) that is deposited onto spliced mRNAs upstream of exon–exon junctions plays important roles in multiple post-splicing gene expression events, such as mRNA export, surveillance, localization, and translation. However, a direct role for the human EJC in pre-mRNA splicing has not been fully understood. Using HeLa cells, we depleted one of the EJC core components, Y14, and the resulting transcriptome was analyzed by deep sequencing (RNA-Seq) and confirmed by RT–PCR. We found that Y14 is required for efficient and faithful splicing of a group of transcripts that is enriched in short intron-containing genes involved in mitotic cell-cycle progression. Tethering of EJC core components (Y14, eIF4AIII or MAGOH) to a model reporter pre-mRNA harboring a short intron showed that these core components are prerequisites for the splicing activation. Taken together, we conclude that the EJC core assembled on pre-mRNA is critical for efficient and faithful splicing of a specific subset of short introns in mitotic cell cycle-related genes. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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2444 KiB  
Article
The OsCYP19-4 Gene Is Expressed as Multiple Alternatively Spliced Transcripts Encoding Isoforms with Distinct Cellular Localizations and PPIase Activities under Cold Stress
by Areum Lee, Sang Sook Lee, Won Yong Jung, Hyun Ji Park, Bo Ra Lim, Hyun-Soon Kim, Jun Cheul Ahn and Hye Sun Cho
Int. J. Mol. Sci. 2016, 17(7), 1154; https://doi.org/10.3390/ijms17071154 - 19 Jul 2016
Cited by 12 | Viewed by 4979
Abstract
Alternative splicing (AS) is an important molecular mechanism by which single genes can generate multiple mRNA isoforms. We reported previously that, in Oryza sativa, the cyclophilin 19-4 (OsCYP19-4.1) transcript was significantly upregulated in response to cold stress, and that transgenic [...] Read more.
Alternative splicing (AS) is an important molecular mechanism by which single genes can generate multiple mRNA isoforms. We reported previously that, in Oryza sativa, the cyclophilin 19-4 (OsCYP19-4.1) transcript was significantly upregulated in response to cold stress, and that transgenic plants were cold tolerant. Here we show that, under cold stress, OsCYP19-4 produces eight transcript variants by intron retention and exon skipping, resulting in production of four distinct protein isoforms. The OsCYP19-4 AS isoforms exhibited different cellular localizations in the epidermal cells: in contrast to OsCYP19-4.1, the OsCYP19-4.2 and OsCYP19-4.3 proteins were primarily targeted to guard and subsidiary cells, whereas OsCYP19-4.5, which consists largely of an endoplasmic reticulum (ER) targeting signal, was co-localized with the RFP-BiP marker in the ER. In OsCYP19-4.2, the key residues of the PPIase domain are altered; consistent with this, recombinant OsCYP19-4.2 had significantly lower PPIase activity than OsCYP19-4.1 in vitro. Specific protein-protein interactions between OsCYP19-4.2/3 and AtRCN1 were verified in yeast two-hybrid (Y2H) and bimolecular fluoresence complementation (BiFC assays), although the OsCYP19-4 isoforms could not bind each other. Based on these results, we propose that two OsCYP19-4 AS isoforms, OsCYP19-4.2 and OsCYP19-4.3, play roles linking auxin transport and cold stress via interactions with RCN1. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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Review

Jump to: Research

574 KiB  
Review
Alternative Splicing of hTERT Pre-mRNA: A Potential Strategy for the Regulation of Telomerase Activity
by Xuewen Liu, Yuchuan Wang, Guangming Chang, Feng Wang, Fei Wang and Xin Geng
Int. J. Mol. Sci. 2017, 18(3), 567; https://doi.org/10.3390/ijms18030567 - 07 Mar 2017
Cited by 34 | Viewed by 5075
Abstract
The activation of telomerase is one of the key events in the malignant transition of cells, and the expression of human telomerase reverse transcriptase (hTERT) is indispensable in the process of activating telomerase. The pre-mRNA alternative splicing of hTERT at the post-transcriptional level [...] Read more.
The activation of telomerase is one of the key events in the malignant transition of cells, and the expression of human telomerase reverse transcriptase (hTERT) is indispensable in the process of activating telomerase. The pre-mRNA alternative splicing of hTERT at the post-transcriptional level is one of the mechanisms for the regulation of telomerase activity. Shifts in splicing patterns occur in the development, tumorigenesis, and response to diverse stimuli in a tissue-specific and cell type–specific manner. Despite the regulation of telomerase activity, the alternative splicing of hTERT pre-mRNA may play a role in other cellular functions. Modulating the mode of hTERT pre-mRNA splicing is providing a new precept of therapy for cancer and aging-related diseases. This review focuses on the patterns of hTERT pre-mRNA alternative splicing and their biological functions, describes the potential association between the alternative splicing of hTERT pre-mRNA and telomerase activity, and discusses the possible significance of the alternative splicing of the hTERT pre-mRNA in the diagnosis, therapy, and prognosis of cancer and aging-related diseases. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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3323 KiB  
Review
Alternative Splicing in Plant Genes: A Means of Regulating the Environmental Fitness of Plants
by Xudong Shang, Ying Cao and Ligeng Ma
Int. J. Mol. Sci. 2017, 18(2), 432; https://doi.org/10.3390/ijms18020432 - 20 Feb 2017
Cited by 123 | Viewed by 14270
Abstract
Gene expression can be regulated through transcriptional and post-transcriptional mechanisms. Transcription in eukaryotes produces pre-mRNA molecules, which are processed and spliced post-transcriptionally to create translatable mRNAs. More than one mRNA may be produced from a single pre-mRNA by alternative splicing (AS); thus, AS [...] Read more.
Gene expression can be regulated through transcriptional and post-transcriptional mechanisms. Transcription in eukaryotes produces pre-mRNA molecules, which are processed and spliced post-transcriptionally to create translatable mRNAs. More than one mRNA may be produced from a single pre-mRNA by alternative splicing (AS); thus, AS serves to diversify an organism’s transcriptome and proteome. Previous studies of gene expression in plants have focused on the role of transcriptional regulation in response to environmental changes. However, recent data suggest that post-transcriptional regulation, especially AS, is necessary for plants to adapt to a changing environment. In this review, we summarize recent advances in our understanding of AS during plant development in response to environmental changes. We suggest that alternative gene splicing is a novel means of regulating the environmental fitness of plants. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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841 KiB  
Review
Role of Splice Variants of Gtf2i, a Transcription Factor Localizing at Postsynaptic Sites, and Its Relation to Neuropsychiatric Diseases
by Yoshinori Shirai, Weidong Li and Tatsuo Suzuki
Int. J. Mol. Sci. 2017, 18(2), 411; https://doi.org/10.3390/ijms18020411 - 15 Feb 2017
Cited by 5 | Viewed by 5617
Abstract
We previously reported that various mRNAs were associated with postsynaptic density (PSD) purified from rat forebrain. Among the thousands of PSD-associated mRNAs, we highlight the biology of the general transcription factor II-I (Gtf2i) mRNA, focusing on the significance of its versatile [...] Read more.
We previously reported that various mRNAs were associated with postsynaptic density (PSD) purified from rat forebrain. Among the thousands of PSD-associated mRNAs, we highlight the biology of the general transcription factor II-I (Gtf2i) mRNA, focusing on the significance of its versatile splicing for targeting its own mRNA into dendrites, regulation of translation, and the effects of Gtf2i expression level as well as its relationship with neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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1506 KiB  
Review
Splice Variants of the RTK Family: Their Role in Tumour Progression and Response to Targeted Therapy
by Cherine Abou-Fayçal, Anne-Sophie Hatat, Sylvie Gazzeri and Beatrice Eymin
Int. J. Mol. Sci. 2017, 18(2), 383; https://doi.org/10.3390/ijms18020383 - 11 Feb 2017
Cited by 38 | Viewed by 6519
Abstract
Receptor tyrosine kinases (RTKs) belong to a family of transmembrane receptors that display tyrosine kinase activity and trigger the activation of downstream signalling pathways mainly involved in cell proliferation and survival. RTK amplification or somatic mutations leading to their constitutive activation and oncogenic [...] Read more.
Receptor tyrosine kinases (RTKs) belong to a family of transmembrane receptors that display tyrosine kinase activity and trigger the activation of downstream signalling pathways mainly involved in cell proliferation and survival. RTK amplification or somatic mutations leading to their constitutive activation and oncogenic properties have been reported in various tumour types. Numerous RTK-targeted therapies have been developed to counteract this hyperactivation. Alternative splicing of pre-mRNA has recently emerged as an important contributor to cancer development and tumour maintenance. Interestingly, RTKs are alternatively spliced. However, the biological functions of RTK splice variants, as well as the upstream signals that control their expression in tumours, remain to be understood. More importantly, it remains to be determined whether, and how, these splicing events may affect the response of tumour cells to RTK-targeted therapies, and inversely, whether these therapies may impact these splicing events. In this review, we will discuss the role of alternative splicing of RTKs in tumour progression and response to therapies, with a special focus on two major RTKs that control proliferation, survival, and angiogenesis, namely, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-1 (VEGFR1). Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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1831 KiB  
Review
Splicing and Polyadenylation of Human Papillomavirus Type 16 mRNAs
by Chengjun Wu, Naoko Kajitani and Stefan Schwartz
Int. J. Mol. Sci. 2017, 18(2), 366; https://doi.org/10.3390/ijms18020366 - 09 Feb 2017
Cited by 31 | Viewed by 5156
Abstract
The human papillomavirus type 16 (HPV16) life cycle can be divided into an early stage in which the HPV16 genomic DNA is replicated, and a late stage in which the HPV16 structural proteins are synthesized and virions are produced. A strong coupling between [...] Read more.
The human papillomavirus type 16 (HPV16) life cycle can be divided into an early stage in which the HPV16 genomic DNA is replicated, and a late stage in which the HPV16 structural proteins are synthesized and virions are produced. A strong coupling between the viral life cycle and the differentiation state of the infected cell is highly characteristic of all HPVs. The switch from the HPV16 early gene expression program to the late requires a promoter switch, a polyadenylation signal switch and a shift in alternative splicing. A number of cis-acting RNA elements on the HPV16 mRNAs and cellular and viral factors interacting with these elements are involved in the control of HPV16 gene expression. This review summarizes our knowledge of HPV16 cis-acting RNA elements and cellular and viral trans-acting factors that regulate HPV16 gene expression at the level of splicing and polyadenylation. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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3399 KiB  
Review
LOX-1 and Its Splice Variants: A New Challenge for Atherosclerosis and Cancer-Targeted Therapies
by Barbara Rizzacasa, Elena Morini, Sabina Pucci, Michela Murdocca, Giuseppe Novelli and Francesca Amati
Int. J. Mol. Sci. 2017, 18(2), 290; https://doi.org/10.3390/ijms18020290 - 29 Jan 2017
Cited by 31 | Viewed by 8694
Abstract
Alternative splicing (AS) is a process in which precursor messenger RNA (pre-mRNA) splicing sites are differentially selected to diversify the protein isoform population. Changes in AS patterns have an essential role in normal development, differentiation and response to physiological stimuli. It is documented [...] Read more.
Alternative splicing (AS) is a process in which precursor messenger RNA (pre-mRNA) splicing sites are differentially selected to diversify the protein isoform population. Changes in AS patterns have an essential role in normal development, differentiation and response to physiological stimuli. It is documented that AS can generate both “risk” and “protective” splice variants that can contribute to the pathogenesis of several diseases including atherosclerosis. The main endothelial receptor for oxidized low-density lipoprotein (ox-LDLs) is LOX-1 receptor protein encoded by the OLR1 gene. When OLR1 undergoes AS events, it generates three variants: OLR1, OLR1D4 and LOXIN. The latter lacks exon 5 and two-thirds of the functional domain. Literature data demonstrate a protective role of LOXIN in pathologies correlated with LOX-1 overexpression such as atherosclerosis and tumors. In this review, we summarize recent developments in understanding of OLR1 AS while also highlighting data warranting further investigation of this process as a novel therapeutic target. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2016)
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