Special Issue "RNA-Binding Proteins—Structure, Function, Networks and Disease"

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

Deadline for manuscript submissions: closed (31 March 2015)

Special Issue Editor

Guest Editor
Prof. Dr. André P. Gerber

Faculty of Health and Medical Sciences, Department of Microbial and Cellular Sciences, School of Biosciences and Medicine, University of Surrey, Stag Hill Campus 19 AX 01, Guildford, GU2 7XH, UK
Website | E-Mail
Fax: +44-(0) 1483 686401
Interests: posttranscriptional gene regulation; RNA-binding proteins; non-coding RNA; translational control; ribonomics

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

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 650 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

Jump to: Review

Open AccessArticle HIV-1 Recruits UPF1 but Excludes UPF2 to Promote Nucleocytoplasmic Export of the Genomic RNA
Biomolecules 2015, 5(4), 2808-2839; doi:10.3390/biom5042808
Received: 7 July 2015 / Revised: 9 September 2015 / Accepted: 16 September 2015 / Published: 20 October 2015
Cited by 6 | PDF Full-text (6665 KB) | HTML Full-text | XML Full-text | Supplementary Files
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)
Open AccessArticle Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1) in Colorectal Cancer Cells
Biomolecules 2015, 5(3), 2035-2055; doi:10.3390/biom5032035
Received: 21 May 2015 / Revised: 30 July 2015 / Accepted: 10 August 2015 / Published: 28 August 2015
Cited by 10 | PDF Full-text (2288 KB) | HTML Full-text | XML Full-text
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)
Open AccessArticle Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins
Biomolecules 2015, 5(3), 1441-1466; doi:10.3390/biom5031441
Received: 10 May 2015 / Accepted: 15 June 2015 / Published: 15 July 2015
Cited by 6 | PDF Full-text (2421 KB) | HTML Full-text | XML Full-text | Supplementary Files
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)
Figures

Open AccessArticle Knockout of RNA Binding Protein MSI2 Impairs Follicle Development in the Mouse Ovary: Characterization of MSI1 and MSI2 during Folliculogenesis
Biomolecules 2015, 5(3), 1228-1244; doi:10.3390/biom5031228
Received: 11 March 2015 / Revised: 29 May 2015 / Accepted: 9 June 2015 / Published: 26 June 2015
Cited by 3 | PDF Full-text (3815 KB) | HTML Full-text | XML Full-text | Supplementary Files
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)
Open AccessArticle RNA-Binding Proteins: Splicing Factors and Disease
Biomolecules 2015, 5(2), 893-909; doi:10.3390/biom5020893
Received: 1 April 2015 / Revised: 22 April 2015 / Accepted: 29 April 2015 / Published: 13 May 2015
Cited by 8 | PDF Full-text (1624 KB) | HTML Full-text | XML Full-text
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)
Open AccessArticle Growth Factor Dependent Regulation of Centrosome Function and Genomic Instability by HuR
Biomolecules 2015, 5(1), 263-281; doi:10.3390/biom5010263
Received: 22 December 2014 / Revised: 6 March 2015 / Accepted: 11 March 2015 / Published: 20 March 2015
Cited by 4 | PDF Full-text (1059 KB) | HTML Full-text | XML Full-text
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)

Review

Jump to: Research

Open AccessReview RNA-Binding Proteins in Trichomonas vaginalis: Atypical Multifunctional Proteins
Biomolecules 2015, 5(4), 3354-3395; doi:10.3390/biom5043354
Received: 21 September 2015 / Revised: 7 November 2015 / Accepted: 12 November 2015 / Published: 26 November 2015
Cited by 2 | PDF Full-text (1897 KB) | HTML Full-text | XML Full-text
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)
Figures

Open AccessReview Competing Interactions of RNA-Binding Proteins, MicroRNAs, and Their Targets Control Neuronal Development and Function
Biomolecules 2015, 5(4), 2903-2918; doi:10.3390/biom5042903
Received: 4 August 2015 / Revised: 15 September 2015 / Accepted: 25 September 2015 / Published: 23 October 2015
Cited by 13 | PDF Full-text (153 KB) | HTML Full-text | XML Full-text
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)
Figures

Open AccessReview The La-Related Proteins, a Family with Connections to Cancer
Biomolecules 2015, 5(4), 2701-2722; doi:10.3390/biom5042701
Received: 6 August 2015 / Revised: 21 September 2015 / Accepted: 7 October 2015 / Published: 16 October 2015
Cited by 18 | PDF Full-text (528 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview RNA-Binding Proteins in the Regulation of miRNA Activity: A Focus on Neuronal Functions
Biomolecules 2015, 5(4), 2363-2387; doi:10.3390/biom5042363
Received: 28 May 2015 / Revised: 16 September 2015 / Accepted: 23 September 2015 / Published: 30 September 2015
PDF Full-text (787 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview New Insights into the Biological Role of Mammalian ADARs; the RNA Editing Proteins
Biomolecules 2015, 5(4), 2338-2362; doi:10.3390/biom5042338
Received: 24 July 2015 / Revised: 9 September 2015 / Accepted: 11 September 2015 / Published: 30 September 2015
Cited by 17 | PDF Full-text (826 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Combinatorial Control of mRNA Fates by RNA-Binding Proteins and Non-Coding RNAs
Biomolecules 2015, 5(4), 2207-2222; doi:10.3390/biom5042207
Received: 17 July 2015 / Revised: 2 September 2015 / Accepted: 8 September 2015 / Published: 24 September 2015
Cited by 15 | PDF Full-text (249 KB) | HTML Full-text | XML Full-text
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)
Figures

Open AccessReview Pre-mRNA Splicing in Plants: In Vivo Functions of RNA-Binding Proteins Implicated in the Splicing Process
Biomolecules 2015, 5(3), 1717-1740; doi:10.3390/biom5031717
Received: 29 May 2015 / Revised: 16 July 2015 / Accepted: 20 July 2015 / Published: 24 July 2015
Cited by 14 | PDF Full-text (402 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Functional Integration of mRNA Translational Control Programs
Biomolecules 2015, 5(3), 1580-1599; doi:10.3390/biom5031580
Received: 22 April 2015 / Revised: 20 June 2015 / Accepted: 14 July 2015 / Published: 21 July 2015
PDF Full-text (879 KB) | HTML Full-text | XML Full-text | Supplementary Files
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)
Figures

Open AccessReview The 3' to 5' Exoribonuclease DIS3: From Structure and Mechanisms to Biological Functions and Role in Human Disease
Biomolecules 2015, 5(3), 1515-1539; doi:10.3390/biom5031515
Received: 18 May 2015 / Revised: 1 July 2015 / Accepted: 6 July 2015 / Published: 17 July 2015
Cited by 8 | PDF Full-text (3761 KB) | HTML Full-text | XML Full-text
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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Open AccessReview CPSF30 at the Interface of Alternative Polyadenylation and Cellular Signaling in Plants
Biomolecules 2015, 5(2), 1151-1168; doi:10.3390/biom5021151
Received: 30 March 2015 / Revised: 26 May 2015 / Accepted: 29 May 2015 / Published: 8 June 2015
Cited by 11 | PDF Full-text (1539 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview Roles of Prolyl Isomerases in RNA-Mediated Gene Expression
Biomolecules 2015, 5(2), 974-999; doi:10.3390/biom5020974
Received: 31 March 2015 / Revised: 1 May 2015 / Accepted: 7 May 2015 / Published: 18 May 2015
Cited by 2 | PDF Full-text (2594 KB) | HTML Full-text | XML Full-text
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)
Open AccessReview RNA-Mediated Regulation of HMGA1 Function
Biomolecules 2015, 5(2), 943-957; doi:10.3390/biom5020943
Received: 31 March 2015 / Accepted: 5 May 2015 / Published: 14 May 2015
Cited by 9 | PDF Full-text (697 KB) | HTML Full-text | XML Full-text
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
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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)
Open AccessReview RNA Binding Proteins that Control Human Papillomavirus Gene Expression
Biomolecules 2015, 5(2), 758-774; doi:10.3390/biom5020758
Received: 17 March 2015 / Revised: 15 April 2015 / Accepted: 21 April 2015 / Published: 5 May 2015
Cited by 7 | PDF Full-text (182 KB) | HTML Full-text | XML Full-text
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
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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)
Open AccessReview Gemin5: A Multitasking RNA-Binding Protein Involved in Translation Control
Biomolecules 2015, 5(2), 528-544; doi:10.3390/biom5020528
Received: 23 March 2015 / Revised: 1 April 2015 / Accepted: 9 April 2015 / Published: 17 April 2015
Cited by 7 | PDF Full-text (2183 KB) | HTML Full-text | XML Full-text
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)
Figures

Open AccessReview Regulation of AU-Rich Element RNA Binding Proteins by Phosphorylation and the Prolyl Isomerase Pin1
Biomolecules 2015, 5(2), 412-434; doi:10.3390/biom5020412
Received: 4 March 2015 / Revised: 23 March 2015 / Accepted: 31 March 2015 / Published: 14 April 2015
Cited by 6 | PDF Full-text (150 KB) | HTML Full-text | XML Full-text
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
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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)
Open AccessReview Function and Pathological Implications of Exon Junction Complex Factor Y14
Biomolecules 2015, 5(2), 343-355; doi:10.3390/biom5020343
Received: 26 February 2015 / Revised: 31 March 2015 / Accepted: 1 April 2015 / Published: 10 April 2015
Cited by 5 | PDF Full-text (158 KB) | HTML Full-text | XML Full-text
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)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: Roles of prolyl isomerases in RNA-mediated gene expression and implications for development of novel therapeutics
Authors: Roopa Thapar
Affiliation: BioSciences at Rice-Biochemistry and Cell Biology, Rice University, Houston, Texas 77251-1892, USA; E-Mail: rthapar@rice.edu
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 17 cyclophilins, 18 FKBPs and at least 3 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 splicesosome 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. The functions of ribonucleoprotein associated PPIases are largely unknown. This review highlights the PPIase genes that play roles in RNA-mediated gene expression, providing insight into their structures, functions and mechanisms of action in vivo.

Type of Paper: Review
Title:
Gemin5, a Multitasking RNA-binding Protein Involved in IRES-dependent Translation
Authors:
David Piñeiro 1,*, Javier Fernandez-Chamorro 2, Rosario Francisco-Velilla 2 and Encarna Martinez-Salas 2
Affiliation:
1 Medical Research Council Toxicology Unit, Lancaster Rd, Leicester LE1 9HN, UK; 2 Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid, Cantoblanco 28049 Madrid, Spain; E-Mail: dpdr1@leicester.ac.uk (D.P.)
Abstract:
Gemin5 is a RNA-binding protein 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 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 eukaryotic initiation factor 4E (eIF4E). Gemin5 was also shown to down-regulate translation, to be a substrate of the picornavirus L protease, and to interact with viral internal ribosome entry site (IRES) elements via two non-canonical RNA binding sites located at its carboxy-terminal end. All these features link Gemin5 with translation events. Thus, beyond its role in snRNPs biogenesis, Gemin5 appears to be a multitasking protein. In this review, we will summarise the knowledge of Gemin5 functions. We will focus on the function of the protein on translation control and discuss how the proteolysis of this RNA binding protein modulates its repressor effect during picornavirus infection.

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