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Biomolecules
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RNA-Binding Proteins—Structure, Function, Networks and Disease
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RNA-Binding Proteins—Structure, Function, Networks and Disease

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 March 2015) | Viewed by 200644

Special Issue Editor

Prof. Dr. André P. Gerber

E-Mail Website
Guest Editor
Department of Microbial Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Stag Hill Campus 19AX01, Guildford GU2 7XH, UK
Interests: posttranscriptional gene regulation; RNA-binding proteins; non-coding RNA; translational control; ribonomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

RNA-binding proteins (RBPs) are key players for the post-transcriptional control of gene expression. They each bind to subpopulations of RNAs and thereby direct and coordinate the fate of all types of RNAs existing in our cells. RBPs control mRNA expression by guiding the processing, localisation, translation and eventual decay; and they collaborate with non-coding RNAs to achieve specific gene regulatory functions. The interest in RBPs is thus steadily increasing, revealing that they comprise a major class of proteins in all kingdoms of life and that they have widespread implications for cell homeostasis and differentiation, in both development and disease.

This issue intends to present up-to-date reviews about all aspects of RNA-binding proteins, providing an orientation point for investigation of this important class of biomolecules. We thus invite submissions of original research manuscripts (although review manuscripts are welcome as well) that cover but are not restricted to four main areas:

  • Structural aspects of ribonucleoprotein complexes, RBPs or domains thereof; bioinformatics prediction of RBPs as well as engineering of RBPs and potential applications.
  • Molecular functions of RBPs in post-transcriptional control of gene expression, including RNA processing, RNA export/localisation and decay, as well as translational control in eukaryotes or prokaryotes.
  • Global-scale analysis of RBPs and their RNA targets; RNA-protein interaction networks and connectivity to other layers of cellular control.
  • The role of RBPs in development and disease; transfer into clinical practice and drug development.

Prof. Dr. André P. Gerber
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. Biomolecules 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 2700 CHF (Swiss Francs). 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

  • posttranscriptional gene regulation
  • RNA binding domain
  • RNA binding protein
  • Non-coding RNA
  • RNA processing
  • RNA localization
  • RNA decay
  • ribonucleoprotein (RNP)
  • translational regulation
  • ribonomics

Published Papers (22 papers)

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Research

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6665 KiB  
Article
HIV-1 Recruits UPF1 but Excludes UPF2 to Promote Nucleocytoplasmic Export of the Genomic RNA
by Lara Ajamian, Karen Abel, Shringar Rao, Kishanda Vyboh, Francisco García-de-Gracia, Ricardo Soto-Rifo, Andreas E. Kulozik, Niels H. Gehring and Andrew J. Mouland
Biomolecules 2015, 5(4), 2808-2839; https://doi.org/10.3390/biom5042808 - 20 Oct 2015
Cited by 46 | Viewed by 8026
Abstract
Unspliced, genomic HIV-1 RNA (vRNA) is a component of several ribonucleoprotein complexes (RNP) during the viral replication cycle. In earlier work, we demonstrated that the host upframeshift protein 1 (UPF1), a key factor in nonsense-mediated mRNA decay (NMD), colocalized and associated to the [...] Read more.
Unspliced, genomic HIV-1 RNA (vRNA) is a component of several ribonucleoprotein complexes (RNP) during the viral replication cycle. In earlier work, we demonstrated that the host upframeshift protein 1 (UPF1), a key factor in nonsense-mediated mRNA decay (NMD), colocalized and associated to the viral structural protein Gag during viral egress. In this work, we demonstrate a new function for UPF1 in the regulation of vRNA nuclear export. OPEN ACCESS Biomolecules 2015, 5 2809 We establish that the nucleocytoplasmic shuttling of UPF1 is required for this function and demonstrate that UPF1 exists in two essential viral RNPs during the late phase of HIV-1 replication: the first, in a nuclear export RNP that contains Rev, CRM1, DDX3 and the nucleoporin p62, and the second, which excludes these nuclear export markers but contains Gag in the cytoplasm. Interestingly, we observed that both UPF2 and the long isoform of UPF3a, UPF3aL, but not the shorter isoforms UPF3aS and UPF3b, are excluded from the UPF1-Rev-CRM1-DDX3 complex as they are negative regulators of vRNA nuclear export. In silico protein-protein docking analyses suggest that Rev binds UPF1 in a region that overlaps the UPF2 binding site, thus explaining the exclusion of this negative regulatory factor by HIV-1 that is necessary for vRNA trafficking. This work uncovers a novel and unique regulatory circuit involving several UPF proteins that ultimately regulate vRNA nuclear export and trafficking. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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2288 KiB  
Article
Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1) in Colorectal Cancer Cells
by Cyril Sobolewski, Sandhya Sanduja, Fernando F. Blanco, Liangyan Hu and Dan A. Dixon
Biomolecules 2015, 5(3), 2035-2055; https://doi.org/10.3390/biom5032035 - 28 Aug 2015
Cited by 33 | Viewed by 6691
Abstract
The RNA-binding protein tristetraprolin (TTP) promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE). In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC) inhibitors [...] Read more.
The RNA-binding protein tristetraprolin (TTP) promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE). In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC) inhibitors (Trichostatin A, SAHA and sodium butyrate) promote TTP expression in colorectal cancer cells (HCA-7, HCT-116, Moser and SW480 cells) and cervix carcinoma cells (HeLa). We found that HDAC inhibitors-induced TTP expression, promote the decay of COX-2 mRNA, and inhibit cancer cell proliferation. HDAC inhibitors were found to promote TTP transcription through activation of the transcription factor Early Growth Response protein 1 (EGR1). Altogether, our findings indicate that loss of TTP in tumors occurs through silencing of EGR1 and suggests a therapeutic approach to rescue TTP expression in colorectal cancer. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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2421 KiB  
Article
Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins
by Rebecca Bish, Nerea Cuevas-Polo, Zhe Cheng, Dolores Hambardzumyan, Mathias Munschauer, Markus Landthaler and Christine Vogel
Biomolecules 2015, 5(3), 1441-1466; https://doi.org/10.3390/biom5031441 - 15 Jul 2015
Cited by 23 | Viewed by 9658
Abstract
DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric protein-protein interactome using immunoprecipitation and [...] Read more.
DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric protein-protein interactome using immunoprecipitation and mass spectrometry. Using DDX6 as bait, we identify a high-confidence and high-quality set of protein interaction partners which are enriched for functions in RNA metabolism and ribosomal proteins. The screen is highly specific, maximizing the number of true positives, as demonstrated by the validation of 81% (47/58) of the RNA-independent interactors through known functions and interactions. Importantly, we minimize the number of indirect interaction partners through use of a nuclease-based digestion to eliminate RNA. We describe eleven new interactors, including proteins involved in splicing which is an as-yet unknown role for DDX6. We validated and characterized in more detail the interaction of DDX6 with Nuclear fragile X mental retardation-interacting protein 2 (NUFIP2) and with two previously uncharacterized proteins, FAM195A and FAM195B (here referred to as granulin-1 and granulin-2, or GRAN1 and GRAN2). We show that NUFIP2, GRAN1, and GRAN2 are not P-body components, but re-localize to stress granules upon exposure to stress, suggesting a function in translation repression in the cellular stress response. Using a complementary analysis that resolved DDX6’s multiple complex memberships, we further validated these interaction partners and the presence of splicing factors. As DDX6 also interacts with the E3 SUMO ligase TIF1β, we tested for and observed a significant enrichment of sumoylation amongst DDX6’s interaction partners. Our results represent the most comprehensive screen for direct interaction partners of a key regulator of RNA life cycle and localization, highlighting new stress granule components and possible DDX6 functions—many of which are likely conserved across eukaryotes. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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3815 KiB  
Article
Knockout of RNA Binding Protein MSI2 Impairs Follicle Development in the Mouse Ovary: Characterization of MSI1 and MSI2 during Folliculogenesis
by Jessie M. Sutherland, Alexander P. Sobinoff, Kara M. Gunter, Barbara A. Fraser, Victoria Pye, Ilana R. Bernstein, Evan Boon, Nicole A. Siddall, Luisa I. De Andres, Gary R. Hime, Janet E. Holt, Thomas Graf and Eileen A. McLaughlin
Biomolecules 2015, 5(3), 1228-1244; https://doi.org/10.3390/biom5031228 - 26 Jun 2015
Cited by 14 | Viewed by 8384
Abstract
Characterizing the mechanisms underlying follicle development in the ovary is crucial to understanding female fertility and is an area of increasing research interest. The RNA binding protein Musashi is essential for post-transcriptional regulation of oocyte maturation in Xenopus and is expressed during ovarian [...] Read more.
Characterizing the mechanisms underlying follicle development in the ovary is crucial to understanding female fertility and is an area of increasing research interest. The RNA binding protein Musashi is essential for post-transcriptional regulation of oocyte maturation in Xenopus and is expressed during ovarian development in Drosophila. In mammals Musashi is important for spermatogenesis and male fertility, but its role in the ovary has yet to be characterized. In this study we determined the expression of mammalian Musashi proteins MSI1 and MSI2 during mouse folliculogenesis, and through the use of a MSI2-specific knockout mouse model we identified that MSI2 is essential for normal follicle development. Time-course characterization of MSI1 and MSI2 revealed distinct differences in steady-state mRNA levels and protein expression/localization at important developmental time-points during folliculogenesis. Using a gene-trap mouse model that inactivates Msi2, we observed a significant decrease in ovarian mass, and change in follicle-stage composition due to developmental blocking of antral stage follicles and pre-antral follicle loss through atresia. We also confirmed that hormonally stimulated Msi2-deficient mice produce significantly fewer MII oocytes (60.9% less than controls, p < 0.05). Furthermore, the majority of these oocytes are of poor viability (62.2% non-viable/apoptotic, p < 0.05), which causes a reduction in female fertility evidenced by decreased litter size in Msi2-deficient animals (33.1% reduction to controls, p < 0.05). Our findings indicate that MSI1 and MSI2 display distinct expression profiles during mammalian folliculogenesis and that MSI2 is required for pre-antral follicle development. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Article
RNA-Binding Proteins: Splicing Factors and Disease
by Alger M. Fredericks, Kamil J. Cygan, Brian A. Brown and William G. Fairbrother
Biomolecules 2015, 5(2), 893-909; https://doi.org/10.3390/biom5020893 - 13 May 2015
Cited by 60 | Viewed by 13242
Abstract
Pre-mRNA splicing is mediated by interactions of the Core Spliceosome and an array of accessory RNA binding proteins with cis-sequence elements. Splicing is a major regulatory component in higher eukaryotes. Disruptions in splicing are a major contributor to human disease. One in three [...] Read more.
Pre-mRNA splicing is mediated by interactions of the Core Spliceosome and an array of accessory RNA binding proteins with cis-sequence elements. Splicing is a major regulatory component in higher eukaryotes. Disruptions in splicing are a major contributor to human disease. One in three hereditary disease alleles are believed to cause aberrant splicing. Hereditary disease alleles can alter splicing by disrupting a splicing element, creating a toxic RNA, or affecting splicing factors. One of the challenges of medical genetics is identifying causal variants from the thousands of possibilities discovered in a clinical sequencing experiment. Here we review the basic biochemistry of splicing, the mechanisms of splicing mutations, the methods for identifying splicing mutants, and the potential of therapeutic interventions. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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1059 KiB  
Article
Growth Factor Dependent Regulation of Centrosome Function and Genomic Instability by HuR
by Natalia Filippova, Xiuhua Yang and Louis Burt Nabors
Biomolecules 2015, 5(1), 263-281; https://doi.org/10.3390/biom5010263 - 20 Mar 2015
Cited by 15 | Viewed by 6627
Abstract
The mRNA binding protein HuR is over expressed in cancer cells and contributes to disease progression through post-transcriptional regulation of mRNA. The regulation of HuR and how this relates to glioma is the focus of this report. SRC and c-Abl kinases regulate HuR [...] Read more.
The mRNA binding protein HuR is over expressed in cancer cells and contributes to disease progression through post-transcriptional regulation of mRNA. The regulation of HuR and how this relates to glioma is the focus of this report. SRC and c-Abl kinases regulate HuR sub-cellular trafficking and influence accumulation in the pericentriolar matrix (PCM) via a growth factor dependent signaling mechanism. Growth factor stimulation of glioma cell lines results in the associate of HuR with the PCM and amplification of centrosome number. This process is regulated by tyrosine phosphorylation of HuR and is abolished by mutating tyrosine residues. HuR is overexpressed in tumor samples from patients with glioblastoma and associated with a reduced survival. These findings suggest HuR plays a significant role in centrosome amplification and genomic instability, which contributes to a worse disease outcome. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Review

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2353 KiB  
Review
RNA-Binding Proteins in Trichomonas vaginalis: Atypical Multifunctional Proteins
by Elisa E. Figueroa-Angulo, Jaeson S. Calla-Choque, Maria Inocente Mancilla-Olea and Rossana Arroyo
Biomolecules 2015, 5(4), 3354-3395; https://doi.org/10.3390/biom5043354 - 26 Nov 2015
Cited by 14 | Viewed by 11027
Abstract
Iron homeostasis is highly regulated in vertebrates through a regulatory system mediated by RNA-protein interactions between the iron regulatory proteins (IRPs) that interact with an iron responsive element (IRE) located in certain mRNAs, dubbed the IRE-IRP regulatory system. Trichomonas vaginalis, the causal [...] Read more.
Iron homeostasis is highly regulated in vertebrates through a regulatory system mediated by RNA-protein interactions between the iron regulatory proteins (IRPs) that interact with an iron responsive element (IRE) located in certain mRNAs, dubbed the IRE-IRP regulatory system. Trichomonas vaginalis, the causal agent of trichomoniasis, presents high iron dependency to regulate its growth, metabolism, and virulence properties. Although T. vaginalis lacks IRPs or proteins with aconitase activity, possesses gene expression mechanisms of iron regulation at the transcriptional and posttranscriptional levels. However, only one gene with iron regulation at the transcriptional level has been described. Recently, our research group described an iron posttranscriptional regulatory mechanism in the T. vaginalis tvcp4 and tvcp12 cysteine proteinase mRNAs. The tvcp4 and tvcp12 mRNAs have a stem-loop structure in the 5'-coding region or in the 3'-UTR, respectively that interacts with T. vaginalis multifunctional proteins HSP70, α-Actinin, and Actin under iron starvation condition, causing translation inhibition or mRNA stabilization similar to the previously characterized IRE-IRP system in eukaryotes. Herein, we summarize recent progress and shed some light on atypical RNA-binding proteins that may participate in the iron posttranscriptional regulation in T. vaginalis. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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153 KiB  
Review
Competing Interactions of RNA-Binding Proteins, MicroRNAs, and Their Targets Control Neuronal Development and Function
by Amy S. Gardiner, Jeffery L. Twiss and Nora I. Perrone-Bizzozero
Biomolecules 2015, 5(4), 2903-2918; https://doi.org/10.3390/biom5042903 - 23 Oct 2015
Cited by 52 | Viewed by 8492
Abstract
Post-transcriptional mechanisms play critical roles in the control of gene expression during neuronal development and maturation as they allow for faster responses to environmental cues and provide spatially-restricted compartments for local control of protein expression. These mechanisms depend on the interaction of cis [...] Read more.
Post-transcriptional mechanisms play critical roles in the control of gene expression during neuronal development and maturation as they allow for faster responses to environmental cues and provide spatially-restricted compartments for local control of protein expression. These mechanisms depend on the interaction of cis-acting elements present in the mRNA sequence and trans-acting factors, such as RNA-binding proteins (RBPs) and microRNAs (miRNAs) that bind to those cis-elements and regulate mRNA stability, subcellular localization, and translation. Recent studies have uncovered an unexpected complexity in these interactions, where coding and non-coding RNAs, termed competing endogenous RNAs (ceRNAs), compete for binding to miRNAs. This competition can, thereby, control a larger number of miRNA target transcripts. However, competing RNA networks also extend to competition between target mRNAs for binding to limited amounts of RBPs. In this review, we present evidence that competitions between target mRNAs for binding to RBPs also occur in neurons, where they affect transcript stability and transport into axons and dendrites as well as translation. In addition, we illustrate the complexity of these mechanisms by demonstrating that RBPs and miRNAs also compete for target binding and regulation. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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528 KiB  
Review
The La-Related Proteins, a Family with Connections to Cancer
by Chara Stavraka and Sarah Blagden
Biomolecules 2015, 5(4), 2701-2722; https://doi.org/10.3390/biom5042701 - 16 Oct 2015
Cited by 83 | Viewed by 11330
Abstract
The evolutionarily-conserved La-related protein (LARP) family currently comprises Genuine La, LARP1, LARP1b, LARP4, LARP4b, LARP6 and LARP7. Emerging evidence suggests each LARP has a distinct role in transcription and/or mRNA translation that is attributable to subtle sequence variations within their La modules and [...] Read more.
The evolutionarily-conserved La-related protein (LARP) family currently comprises Genuine La, LARP1, LARP1b, LARP4, LARP4b, LARP6 and LARP7. Emerging evidence suggests each LARP has a distinct role in transcription and/or mRNA translation that is attributable to subtle sequence variations within their La modules and specific C-terminal domains. As emerging research uncovers the function of each LARP, it is evident that La, LARP1, LARP6, LARP7 and possibly LARP4a and 4b are dysregulated in cancer. Of these, LARP1 is the first to be demonstrated to drive oncogenesis. Here, we review the role of each LARP and the evidence linking it to malignancy. We discuss a future strategy of targeting members of this protein family as cancer therapy. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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787 KiB  
Review
RNA-Binding Proteins in the Regulation of miRNA Activity: A Focus on Neuronal Functions
by Alessia Loffreda, Aurora Rigamonti, Silvia M. L. Barabino and Silvia C. Lenzken
Biomolecules 2015, 5(4), 2363-2387; https://doi.org/10.3390/biom5042363 - 30 Sep 2015
Cited by 32 | Viewed by 9763
Abstract
Posttranscriptional modifications of messenger RNAs (mRNAs) are key processes in the fine-tuning of cellular homeostasis. Two major actors in this scenario are RNA binding proteins (RBPs) and microRNAs (miRNAs) that together play important roles in the biogenesis, turnover, translation and localization of mRNAs. [...] Read more.
Posttranscriptional modifications of messenger RNAs (mRNAs) are key processes in the fine-tuning of cellular homeostasis. Two major actors in this scenario are RNA binding proteins (RBPs) and microRNAs (miRNAs) that together play important roles in the biogenesis, turnover, translation and localization of mRNAs. This review will highlight recent advances in the understanding of the role of RBPs in the regulation of the maturation and the function of miRNAs. The interplay between miRNAs and RBPs is discussed specifically in the context of neuronal development and function. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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826 KiB  
Review
New Insights into the Biological Role of Mammalian ADARs; the RNA Editing Proteins
by Niamh Mannion, Fabiana Arieti, Angela Gallo, Liam P. Keegan and Mary A. O'Connell
Biomolecules 2015, 5(4), 2338-2362; https://doi.org/10.3390/biom5042338 - 30 Sep 2015
Cited by 60 | Viewed by 10346
Abstract
The ADAR proteins deaminate adenosine to inosine in double-stranded RNA which is one of the most abundant modifications present in mammalian RNA. Inosine can have a profound effect on the RNAs that are edited, not only changing the base-pairing properties, but can also [...] Read more.
The ADAR proteins deaminate adenosine to inosine in double-stranded RNA which is one of the most abundant modifications present in mammalian RNA. Inosine can have a profound effect on the RNAs that are edited, not only changing the base-pairing properties, but can also result in recoding, as inosine behaves as if it were guanosine. In mammals there are three ADAR proteins and two ADAR-related proteins (ADAD) expressed. All have a very similar modular structure; however, both their expression and biological function differ significantly. Only two of the ADAR proteins have enzymatic activity. However, both ADAR and ADAD proteins possess the ability to bind double-strand RNA. Mutations in ADARs have been associated with many diseases ranging from cancer, innate immunity to neurological disorders. Here, we will discuss in detail the domain structure of mammalian ADARs, the effects of RNA editing, and the role of ADARs in human diseases. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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249 KiB  
Review
Combinatorial Control of mRNA Fates by RNA-Binding Proteins and Non-Coding RNAs
by Valentina Iadevaia and André P. Gerber
Biomolecules 2015, 5(4), 2207-2222; https://doi.org/10.3390/biom5042207 - 24 Sep 2015
Cited by 60 | Viewed by 7877
Abstract
Post-transcriptional control of gene expression is mediated by RNA-binding proteins (RBPs) and small non-coding RNAs (e.g., microRNAs) that bind to distinct elements in their mRNA targets. Here, we review recent examples describing the synergistic and/or antagonistic effects mediated by RBPs and miRNAs to [...] Read more.
Post-transcriptional control of gene expression is mediated by RNA-binding proteins (RBPs) and small non-coding RNAs (e.g., microRNAs) that bind to distinct elements in their mRNA targets. Here, we review recent examples describing the synergistic and/or antagonistic effects mediated by RBPs and miRNAs to determine the localisation, stability and translation of mRNAs in mammalian cells. From these studies, it is becoming increasingly apparent that dynamic rearrangements of RNA-protein complexes could have profound implications in human cancer, in synaptic plasticity, and in cellular differentiation. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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402 KiB  
Review
Pre-mRNA Splicing in Plants: In Vivo Functions of RNA-Binding Proteins Implicated in the Splicing Process
by Katja Meyer, Tino Koester and Dorothee Staiger
Biomolecules 2015, 5(3), 1717-1740; https://doi.org/10.3390/biom5031717 - 24 Jul 2015
Cited by 59 | Viewed by 13500
Abstract
Alternative pre-messenger RNA splicing in higher plants emerges as an important layer of regulation upon exposure to exogenous and endogenous cues. Accordingly, mutants defective in RNA-binding proteins predicted to function in the splicing process show severe phenotypic alterations. Among those are developmental defects, [...] Read more.
Alternative pre-messenger RNA splicing in higher plants emerges as an important layer of regulation upon exposure to exogenous and endogenous cues. Accordingly, mutants defective in RNA-binding proteins predicted to function in the splicing process show severe phenotypic alterations. Among those are developmental defects, impaired responses to pathogen threat or abiotic stress factors, and misregulation of the circadian timing system. A suite of splicing factors has been identified in the model plant Arabidopsis thaliana. Here we summarize recent insights on how defects in these splicing factors impair plant performance. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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879 KiB  
Review
Functional Integration of mRNA Translational Control Programs
by Melanie C. MacNicol, Chad E. Cragle, Karthik Arumugam, Bruno Fosso, Graziano Pesole and Angus M. MacNicol
Biomolecules 2015, 5(3), 1580-1599; https://doi.org/10.3390/biom5031580 - 21 Jul 2015
Cited by 11 | Viewed by 7305
Abstract
Regulated mRNA translation plays a key role in control of cell cycle progression in a variety of physiological and pathological processes, including in the self-renewal and survival of stem cells and cancer stem cells. While targeting mRNA translation presents an attractive strategy for [...] Read more.
Regulated mRNA translation plays a key role in control of cell cycle progression in a variety of physiological and pathological processes, including in the self-renewal and survival of stem cells and cancer stem cells. While targeting mRNA translation presents an attractive strategy for control of aberrant cell cycle progression, mRNA translation is an underdeveloped therapeutic target. Regulated mRNAs are typically controlled through interaction with multiple RNA binding proteins (RBPs) but the mechanisms by which the functions of distinct RBPs bound to a common target mRNA are coordinated are poorly understood. The challenge now is to gain insight into these mechanisms of coordination and to identify the molecular mediators that integrate multiple, often conflicting, inputs. A first step includes the identification of altered mRNA ribonucleoprotein complex components that assemble on mRNAs bound by multiple, distinct RBPs compared to those recruited by individual RBPs. This review builds upon our knowledge of combinatorial control of mRNA translation during the maturation of oocytes from Xenopus laevis, to address molecular strategies that may mediate RBP diplomacy and conflict resolution for coordinated control of mRNA translational output. Continued study of regulated ribonucleoprotein complex dynamics promises valuable new insights into mRNA translational control and may suggest novel therapeutic strategies for the treatment of disease. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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3761 KiB  
Review
The 3' to 5' Exoribonuclease DIS3: From Structure and Mechanisms to Biological Functions and Role in Human Disease
by Sophie R. Robinson, Antony W. Oliver, Timothy J. Chevassut and Sarah F. Newbury
Biomolecules 2015, 5(3), 1515-1539; https://doi.org/10.3390/biom5031515 - 17 Jul 2015
Cited by 43 | Viewed by 9506
Abstract
DIS3 is a conserved exoribonuclease and catalytic subunit of the exosome, a protein complex involved in the 3' to 5' degradation and processing of both nuclear and cytoplasmic RNA species. Recently, aberrant expression of DIS3 has been found to be implicated in a [...] Read more.
DIS3 is a conserved exoribonuclease and catalytic subunit of the exosome, a protein complex involved in the 3' to 5' degradation and processing of both nuclear and cytoplasmic RNA species. Recently, aberrant expression of DIS3 has been found to be implicated in a range of different cancers. Perhaps most striking is the finding that DIS3 is recurrently mutated in 11% of multiple myeloma patients. Much work has been done to elucidate the structural and biochemical characteristics of DIS3, including the mechanistic details of its role as an effector of RNA decay pathways. Nevertheless, we do not understand how DIS3 mutations can lead to cancer. There are a number of studies that pertain to the function of DIS3 at the organismal level. Mutant phenotypes in S. pombe, S. cerevisiae and Drosophila suggest DIS3 homologues have a common role in cell-cycle progression and microtubule assembly. DIS3 has also recently been implicated in antibody diversification of mouse B-cells. This article aims to review current knowledge of the structure, mechanisms and functions of DIS3 as well as highlighting the genetic patterns observed within myeloma patients, in order to yield insight into the putative role of DIS3 mutations in oncogenesis. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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1539 KiB  
Review
CPSF30 at the Interface of Alternative Polyadenylation and Cellular Signaling in Plants
by Manohar Chakrabarti and Arthur G. Hunt
Biomolecules 2015, 5(2), 1151-1168; https://doi.org/10.3390/biom5021151 - 08 Jun 2015
Cited by 40 | Viewed by 9254
Abstract
Post-transcriptional processing, involving cleavage of precursor messenger RNA (pre mRNA), and further incorporation of poly(A) tail to the 3' end is a key step in the expression of genetic information. Alternative polyadenylation (APA) serves as an important check point for the regulation of [...] Read more.
Post-transcriptional processing, involving cleavage of precursor messenger RNA (pre mRNA), and further incorporation of poly(A) tail to the 3' end is a key step in the expression of genetic information. Alternative polyadenylation (APA) serves as an important check point for the regulation of gene expression. Recent studies have shown widespread prevalence of APA in diverse systems. A considerable amount of research has been done in characterizing different subunits of so-called Cleavage and Polyadenylation Specificity Factor (CPSF). In plants, CPSF30, an ortholog of the 30 kD subunit of mammalian CPSF is a key polyadenylation factor. CPSF30 in the model plant Arabidopsis thaliana was reported to possess unique biochemical properties. It was also demonstrated that poly(A) site choice in a vast majority of genes in Arabidopsis are CPSF30 dependent, suggesting a pivotal role of this gene in APA and subsequent regulation of gene expression. There are also indications of this gene being involved in oxidative stress and defense responses and in cellular signaling, suggesting a role of CPSF30 in connecting physiological processes and APA. This review will summarize the biochemical features of CPSF30, its role in regulating APA, and possible links with cellular signaling and stress response modules. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Review
Roles of Prolyl Isomerases in RNA-Mediated Gene Expression
by Roopa Thapar
Biomolecules 2015, 5(2), 974-999; https://doi.org/10.3390/biom5020974 - 18 May 2015
Cited by 26 | Viewed by 9486
Abstract
The peptidyl-prolyl cis-trans isomerases (PPIases) that include immunophilins (cyclophilins and FKBPs) and parvulins (Pin1, Par14, Par17) participate in cell signaling, transcription, pre-mRNA processing and mRNA decay. The human genome encodes 19 cyclophilins, 18 FKBPs and three parvulins. Immunophilins are receptors for the immunosuppressive [...] Read more.
The peptidyl-prolyl cis-trans isomerases (PPIases) that include immunophilins (cyclophilins and FKBPs) and parvulins (Pin1, Par14, Par17) participate in cell signaling, transcription, pre-mRNA processing and mRNA decay. The human genome encodes 19 cyclophilins, 18 FKBPs and three parvulins. Immunophilins are receptors for the immunosuppressive drugs cyclosporin A, FK506, and rapamycin that are used in organ transplantation. Pin1 has also been targeted in the treatment of Alzheimer’s disease, asthma, and a number of cancers. While these PPIases are characterized as molecular chaperones, they also act in a nonchaperone manner to promote protein-protein interactions using surfaces outside their active sites. The immunosuppressive drugs act by a gain-of-function mechanism by promoting protein-protein interactions in vivo. Several immunophilins have been identified as components of the spliceosome and are essential for alternative splicing. Pin1 plays roles in transcription and RNA processing by catalyzing conformational changes in the RNA Pol II C-terminal domain. Pin1 also binds several RNA binding proteins such as AUF1, KSRP, HuR, and SLBP that regulate mRNA decay by remodeling mRNP complexes. The functions of ribonucleoprotein associated PPIases are largely unknown. This review highlights PPIases that play roles in RNA-mediated gene expression, providing insight into their structures, functions and mechanisms of action in mRNP remodeling in vivo. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Review
RNA-Mediated Regulation of HMGA1 Function
by Arndt G. Benecke and Sebastian Eilebrecht
Biomolecules 2015, 5(2), 943-957; https://doi.org/10.3390/biom5020943 - 14 May 2015
Cited by 28 | Viewed by 7346
Abstract
The high mobility group protein A1 (HMGA1) is a master regulator of chromatin structure mediating its major gene regulatory activity by direct interactions with A/T-rich DNA sequences located in the promoter and enhancer regions of a large variety of genes. HMGA1 DNA-binding through [...] Read more.
The high mobility group protein A1 (HMGA1) is a master regulator of chromatin structure mediating its major gene regulatory activity by direct interactions with A/T-rich DNA sequences located in the promoter and enhancer regions of a large variety of genes. HMGA1 DNA-binding through three AT-hook motifs results in an open chromatin structure and subsequently leads to changes in gene expression. Apart from its significant expression during development, HMGA1 is over-expressed in virtually every cancer, where HMGA1 expression levels correlate with tumor malignancy. The exogenous overexpression of HMGA1 can lead to malignant cell transformation, assigning the protein a key role during cancerogenesis. Recent studies have unveiled highly specific competitive interactions of HMGA1 with cellular and viral RNAs also through an AT-hook domain of the protein, significantly impacting the HMGA1-dependent gene expression. In this review, we discuss the structure and function of HMGA1-RNA complexes during transcription and epigenomic regulation and their implications in HMGA1-related diseases. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Review
RNA Binding Proteins that Control Human Papillomavirus Gene Expression
by Naoko Kajitani and Stefan Schwartz
Biomolecules 2015, 5(2), 758-774; https://doi.org/10.3390/biom5020758 - 05 May 2015
Cited by 19 | Viewed by 6895
Abstract
The human papillomavirus (HPV) life cycle is strictly linked to the differentiation program of the infected mucosal epithelial cell. In the basal and lower levels of the epithelium, early genes coding for pro-mitotic proteins and viral replication factors are expressed, while terminal cell [...] Read more.
The human papillomavirus (HPV) life cycle is strictly linked to the differentiation program of the infected mucosal epithelial cell. In the basal and lower levels of the epithelium, early genes coding for pro-mitotic proteins and viral replication factors are expressed, while terminal cell differentiation is required for activation of late gene expression and production of viral particles at the very top of the epithelium. Such productive infections are normally cleared within 18–24 months. In rare cases, the HPV infection is stuck in the early stage of the infection. Such infections may give rise to cervical lesions that can progress to cancer, primarily cancer of the uterine cervix. Since cancer progression is strictly linked to HPV gene expression, it is of interest to understand how HPV gene expression is regulated. Cis-acting HPV RNA elements and cellular RNA-binding proteins control HPV mRNA splicing and polyadenylation. These interactions are believed to play a particularly important role in the switch from early to late gene expression, thereby contributing to the pathogenesis of HPV. Indeed, it has been shown that the levels of various RNA binding proteins change in response to differentiation and in response to HPV induced cervical lesions and cancer. Here we have compiled published data on RNA binding proteins involved in the regulation of HPV gene expression. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Review
Gemin5: A Multitasking RNA-Binding Protein Involved in Translation Control
by David Piñeiro, Javier Fernandez-Chamorro, Rosario Francisco-Velilla and Encarna Martinez-Salas
Biomolecules 2015, 5(2), 528-544; https://doi.org/10.3390/biom5020528 - 17 Apr 2015
Cited by 29 | Viewed by 8211
Abstract
Gemin5 is a RNA-binding protein (RBP) that was first identified as a peripheral component of the survival of motor neurons (SMN) complex. This predominantly cytoplasmic protein recognises the small nuclear RNAs (snRNAs) through its WD repeat domains, allowing assembly of the SMN complex [...] Read more.
Gemin5 is a RNA-binding protein (RBP) that was first identified as a peripheral component of the survival of motor neurons (SMN) complex. This predominantly cytoplasmic protein recognises the small nuclear RNAs (snRNAs) through its WD repeat domains, allowing assembly of the SMN complex into small nuclear ribonucleoproteins (snRNPs). Additionally, the amino-terminal end of the protein has been reported to possess cap-binding capacity and to interact with the eukaryotic initiation factor 4E (eIF4E). Gemin5 was also shown to downregulate translation, to be a substrate of the picornavirus L protease and to interact with viral internal ribosome entry site (IRES) elements via a bipartite non-canonical RNA-binding site located at its carboxy-terminal end. These features link Gemin5 with translation control events. Thus, beyond its role in snRNPs biogenesis, Gemin5 appears to be a multitasking protein cooperating in various RNA-guided processes. In this review, we will summarise current knowledge of Gemin5 functions. We will discuss the involvement of the protein on translation control and propose a model to explain how the proteolysis fragments of this RBP in picornavirus-infected cells could modulate protein synthesis. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Review
Regulation of AU-Rich Element RNA Binding Proteins by Phosphorylation and the Prolyl Isomerase Pin1
by Zhong-Jian Shen and James S. Malter
Biomolecules 2015, 5(2), 412-434; https://doi.org/10.3390/biom5020412 - 14 Apr 2015
Cited by 31 | Viewed by 10185
Abstract
The accumulation of 3' untranslated region (3'-UTR), AU-rich element (ARE) containing mRNAs, are predominantly controlled at the post-transcriptional level. Regulation appears to rely on a variable and dynamic interaction between mRNA target and ARE-specific binding proteins (AUBPs). The AUBP-ARE mRNA recognition is directed [...] Read more.
The accumulation of 3' untranslated region (3'-UTR), AU-rich element (ARE) containing mRNAs, are predominantly controlled at the post-transcriptional level. Regulation appears to rely on a variable and dynamic interaction between mRNA target and ARE-specific binding proteins (AUBPs). The AUBP-ARE mRNA recognition is directed by multiple intracellular signals that are predominantly targeted at the AUBPs. These include (but are unlikely limited to) methylation, acetylation, phosphorylation, ubiquitination and isomerization. These regulatory events ultimately affect ARE mRNA location, abundance, translation and stability. In this review, we describe recent advances in our understanding of phosphorylation and its impact on conformation of the AUBPs, interaction with ARE mRNAs and highlight the role of Pin1 mediated prolyl cis-trans isomerization in these biological process. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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Review
Function and Pathological Implications of Exon Junction Complex Factor Y14
by Tzu-Wei Chuang, Kou-Ming Lee and Woan-Yuh Tarn
Biomolecules 2015, 5(2), 343-355; https://doi.org/10.3390/biom5020343 - 10 Apr 2015
Cited by 21 | Viewed by 5528
Abstract
Eukaryotic mRNA biogenesis involves a series of interconnected steps, including nuclear pre-mRNA processing, mRNA export, and surveillance. The exon-junction complex (EJC) is deposited on newly spliced mRNAs and coordinates several downstream steps of mRNA biogenesis. The EJC core protein, Y14, functions with its [...] Read more.
Eukaryotic mRNA biogenesis involves a series of interconnected steps, including nuclear pre-mRNA processing, mRNA export, and surveillance. The exon-junction complex (EJC) is deposited on newly spliced mRNAs and coordinates several downstream steps of mRNA biogenesis. The EJC core protein, Y14, functions with its partners in nonsense-mediated mRNA decay and translational enhancement. Y14 plays additional roles in mRNA metabolism, some of which are independent of the EJC, and it is also involved in other cellular processes. Genetic mutations or aberrant expression of Y14 results in physiological abnormality and may cause disease. Therefore, it is important to understand the various functions of Y14 and its physiological and pathological roles. Full article
(This article belongs to the Special Issue RNA-Binding Proteins—Structure, Function, Networks and Disease)
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