ijms-logo

Journal Browser

Journal Browser

RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies

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

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 83738

Special Issue Editors

Medical Faculty, Martin-Luther-University Halle-Wittenberg, Charles Tanford Protein Centre, Halle (Saale), Germany
Interests: cancer biology; metastasis; non-coding RNAs; RNA-binding proteins; functional genomics; genome engineering; CRISPR/Cas9
Special Issues, Collections and Topics in MDPI journals
Institute of Pathology, University Hospital Halle, Halle (Saale), Germany
Interests: cancer research; metastasis; tumor microenvironment; platelets; non-coding RNA; cell signaling

Special Issue Information

Dear Colleagues,

Recent proteome-wide studies have established a comprehensive catalogue of RNA-binding proteins (RBPs) whose functions are largely unknown. In general, RBPs can change the fate or function of their associated RNA cargo, which has significant implications for human diseases. However, our mechanistic understanding of RBP-dependent regulation is still limited, partially due to the pleiotropic nature of RBPs which can regulate a large collection of coding and non-coding transcripts. Hence, studying RBPs requires multidisciplinary and integrative approaches, e.g. systems and structural biology as well as functional genomics and proteomics.

The goal of this Special Issue is to broaden our molecular understanding about the role of RBPs in human diseases as well as to highlight their potential to significantly contribute to personalized precision medicine efforts in the future. Hence, this Special Issue will feature target discovery strategies as well as novel developments in therapeutic and diagnostic approaches based on RBPs for disease detection and treatment, including the use of small molecules, nanomedicine, and biomaterials. We invite authors to submit their original research as well as review articles describing basic and translational findings with a special focus on RBPs and their role in human cancers, as well as cardiovascular and ageing-related diseases.

Prof. Dr. Tony Gutschner
Dr. Monika Hämmerle
Guest Editors

Manuscript Submission Information

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

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

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

Keywords

  • cancer
  • CVD
  • ageing
  • RBP
  • alternative splicing
  • post-transcriptional regulation
  • gene expression networks
  • functional genomics

Published Papers (18 papers)

Order results
Result details
Select all
Export citation of selected articles as:
30 pages, 1750 KiB  
Review
Expression, Regulation and Function of microRNA as Important Players in the Transition of MDS to Secondary AML and Their Cross Talk to RNA-Binding Proteins
by Marcus Bauer, Christoforos Vaxevanis, Nadine Heimer, Haifa Kathrin Al-Ali, Nadja Jaekel, Michael Bachmann, Claudia Wickenhauser and Barbara Seliger
Int. J. Mol. Sci. 2020, 21(19), 7140; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197140 - 27 Sep 2020
Cited by 14 | Viewed by 3488
Abstract
Myelodysplastic syndromes (MDS), heterogeneous diseases of hematopoietic stem cells, exhibit a significant risk of progression to secondary acute myeloid leukemia (sAML) that are typically accompanied by MDS-related changes and therefore significantly differ to de novo acute myeloid leukemia (AML). Within these disorders, the [...] Read more.
Myelodysplastic syndromes (MDS), heterogeneous diseases of hematopoietic stem cells, exhibit a significant risk of progression to secondary acute myeloid leukemia (sAML) that are typically accompanied by MDS-related changes and therefore significantly differ to de novo acute myeloid leukemia (AML). Within these disorders, the spectrum of cytogenetic alterations and oncogenic mutations, the extent of a predisposing defective osteohematopoietic niche, and the irregularity of the tumor microenvironment is highly diverse. However, the exact underlying pathophysiological mechanisms resulting in hematopoietic failure in patients with MDS and sAML remain elusive. There is recent evidence that the post-transcriptional control of gene expression mediated by microRNAs (miRNAs), long noncoding RNAs, and/or RNA-binding proteins (RBPs) are key components in the pathogenic events of both diseases. In addition, an interplay between RBPs and miRNAs has been postulated in MDS and sAML. Although a plethora of miRNAs is aberrantly expressed in MDS and sAML, their expression pattern significantly depends on the cell type and on the molecular make-up of the sample, including chromosomal alterations and single nucleotide polymorphisms, which also reflects their role in disease progression and prediction. Decreased expression levels of miRNAs or RBPs preventing the maturation or inhibiting translation of genes involved in pathogenesis of both diseases were found. Therefore, this review will summarize the current knowledge regarding the heterogeneity of expression, function, and clinical relevance of miRNAs, its link to molecular abnormalities in MDS and sAML with specific focus on the interplay with RBPs, and the current treatment options. This information might improve the use of miRNAs and/or RBPs as prognostic markers and therapeutic targets for both malignancies. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

16 pages, 2875 KiB  
Article
Knockdown of Musashi RNA Binding Proteins Decreases Radioresistance but Enhances Cell Motility and Invasion in Triple-Negative Breast Cancer
by Fabian M. Troschel, Annemarie Minte, Yahia Mahmoud Ismail, Amr Kamal, Mahmoud Salah Abdullah, Sarah Hamdy Ahmed, Marie Deffner, Björn Kemper, Ludwig Kiesel, Hans Theodor Eich, Sherif Abdelaziz Ibrahim, Martin Götte and Burkhard Greve
Int. J. Mol. Sci. 2020, 21(6), 2169; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062169 - 21 Mar 2020
Cited by 24 | Viewed by 4469
Abstract
The therapeutic potential of Musashi (MSI) RNA-binding proteins, important stemness-associated gene expression regulators, remains insufficiently understood in breast cancer. This study identifies the interplay between MSI protein expression, stem cell characteristics, radioresistance, cell invasiveness and migration. MSI-1, MSI-2 and Notch pathway elements were [...] Read more.
The therapeutic potential of Musashi (MSI) RNA-binding proteins, important stemness-associated gene expression regulators, remains insufficiently understood in breast cancer. This study identifies the interplay between MSI protein expression, stem cell characteristics, radioresistance, cell invasiveness and migration. MSI-1, MSI-2 and Notch pathway elements were investigated via quantitative polymerase chain reaction (qPCR) in 19 triple-negative breast cancer samples. Measurements were repeated in MDA-MB-231 cells after MSI-1 and -2 siRNA-mediated double knockdown, with further experiments performed after MSI silencing. Flow cytometry helped quantify expression of CD44 and leukemia inhibitory factor receptor (LIFR), changes in apoptosis and cell cycle progression. Proliferation and irradiation-induced effects were assessed using colony formation assays. Radiation-related proteins were investigated via Western blots. Finally, cell invasion assays and digital holographic microscopy for cell migration were performed. MSI proteins showed strong correlations with Notch pathway elements. MSI knockdown resulted in reduction of stem cell marker expression, cell cycle progression and proliferation, while increasing apoptosis. Cells were radiosensitized as radioresistance-conferring proteins were downregulated. However, MSI-silencing-mediated LIFR downregulation resulted in enhanced cell invasion and migration. We conclude that, while MSI knockdown results in several therapeutically desirable consequences, enhanced invasion and migration need to be counteracted before knockdown advantages can be fully exploited. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

14 pages, 1692 KiB  
Review
The Role of the RNA-Binding Protein Family MEX-3 in Tumorigenesis
by Simon Jasinski-Bergner, André Steven and Barbara Seliger
Int. J. Mol. Sci. 2020, 21(15), 5209; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155209 - 23 Jul 2020
Cited by 13 | Viewed by 2416
Abstract
The muscle excess 3 (MEX-3) protein was first identified in Caenorhabditis elegans (C. elegans), and its respective homologues were also observed in vertebrates, including humans. It is a RNA-binding protein (RBP) with an additional ubiquitin E3 ligase function, which further acts as [...] Read more.
The muscle excess 3 (MEX-3) protein was first identified in Caenorhabditis elegans (C. elegans), and its respective homologues were also observed in vertebrates, including humans. It is a RNA-binding protein (RBP) with an additional ubiquitin E3 ligase function, which further acts as a post-transcriptional repressor through unknown mechanisms. In humans, MEX-3 proteins post-transcriptionally regulate a number of biological processes, including tumor immunological relevant ones. These have been shown to be involved in various diseases, including tumor diseases of distinct origins. This review provides information on the expression and function of the human MEX-3 family in healthy tissues, as well after malignant transformation. Indeed, the MEX-3 expression was shown to be deregulated in several cancers and to affect tumor biological functions, including apoptosis regulation, antigen processing, and presentation, thereby, contributing to the immune evasion of tumor cells. Furthermore, current research suggests MEX-3 proteins as putative markers for prognosis and as novel targets for the anti-cancer treatment. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

17 pages, 2783 KiB  
Article
YBX1 Indirectly Targets Heterochromatin-Repressed Inflammatory Response-Related Apoptosis Genes through Regulating CBX5 mRNA
by Andreas Kloetgen, Sujitha Duggimpudi, Konstantin Schuschel, Kebria Hezaveh, Daniel Picard, Heiner Schaal, Marc Remke, Jan-Henning Klusmann, Arndt Borkhardt, Alice C. McHardy and Jessica I. Hoell
Int. J. Mol. Sci. 2020, 21(12), 4453; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124453 - 23 Jun 2020
Cited by 11 | Viewed by 2882
Abstract
Medulloblastomas arise from undifferentiated precursor cells in the cerebellum and account for about 20% of all solid brain tumors during childhood; standard therapies include radiation and chemotherapy, which oftentimes come with severe impairment of the cognitive development of the young patients. Here, we [...] Read more.
Medulloblastomas arise from undifferentiated precursor cells in the cerebellum and account for about 20% of all solid brain tumors during childhood; standard therapies include radiation and chemotherapy, which oftentimes come with severe impairment of the cognitive development of the young patients. Here, we show that the posttranscriptional regulator Y-box binding protein 1 (YBX1), a DNA- and RNA-binding protein, acts as an oncogene in medulloblastomas by regulating cellular survival and apoptosis. We observed different cellular responses upon YBX1 knockdown in several medulloblastoma cell lines, with significantly altered transcription and subsequent apoptosis rates. Mechanistically, PAR-CLIP for YBX1 and integration with RNA-Seq data uncovered direct posttranscriptional control of the heterochromatin-associated gene CBX5; upon YBX1 knockdown and subsequent CBX5 mRNA instability, heterochromatin-regulated genes involved in inflammatory response, apoptosis and death receptor signaling were de-repressed. Thus, YBX1 acts as an oncogene in medulloblastoma through indirect transcriptional regulation of inflammatory genes regulating apoptosis and represents a promising novel therapeutic target in this tumor entity. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

14 pages, 1703 KiB  
Review
MCPIP1 RNase and Its Multifaceted Role
by Richard Musson, Weronika Szukała and Jolanta Jura
Int. J. Mol. Sci. 2020, 21(19), 7183; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197183 - 29 Sep 2020
Cited by 15 | Viewed by 3433
Abstract
Inflammation is an organism’s physiological response to harmful septic and aseptic stimuli. This process begins locally through the influx of immune system cells to the damaged tissue and the subsequent activation and secretion of inflammatory mediators to restore homeostasis in the organism. Inflammation [...] Read more.
Inflammation is an organism’s physiological response to harmful septic and aseptic stimuli. This process begins locally through the influx of immune system cells to the damaged tissue and the subsequent activation and secretion of inflammatory mediators to restore homeostasis in the organism. Inflammation is regulated at many levels, and one of these levels is post-transcriptional regulation, which controls the half-life of transcripts that encode inflammatory mediators. One of the proteins responsible for controlling the amount of mRNA in a cell is the RNase monocyte chemoattractant protein-induced protein 1 (MCPIP1). The studies conducted so far have shown that MCPIP1 is involved not only in the regulation of inflammation but also in many other physiological and pathological processes. This paper provides a summary of the information on the role of MCPIP1 in adipogenesis, angiogenesis, cell differentiation, cancer, and skin inflammation obtained to date. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

27 pages, 2245 KiB  
Article
Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma
by Jessica L. Bell, Sven Hagemann, Jessica K. Holien, Tao Liu, Zsuzsanna Nagy, Johannes H. Schulte, Danny Misiak and Stefan Hüttelmaier
Int. J. Mol. Sci. 2020, 21(14), 5098; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145098 - 19 Jul 2020
Cited by 12 | Viewed by 3812
Abstract
Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have [...] Read more.
Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have reported roles in neuroblastoma development and patient outcome, the role of RBPs in neuroblastoma is relatively unstudied. In order to elucidate novel RBPs involved in MYCN-amplified and other high-risk neuroblastoma subtypes, we performed differential mRNA expression analysis of RBPs in a large primary tumour cohort (n = 498). Additionally, we found via Kaplan–Meier scanning analysis that 685 of the 1483 tested RBPs have prognostic value in neuroblastoma. For the top putative oncogenic candidates, we analysed their expression in neuroblastoma cell lines, as well as summarised their characteristics and existence of chemical inhibitors. Moreover, to help explain their association with neuroblastoma subtypes, we reviewed candidate RBPs’ potential as biomarkers, and their mechanistic roles in neuronal and cancer contexts. We found several highly significant RBPs including RPL22L1, RNASEH2A, PTRH2, MRPL11 and AFF2, which remain uncharacterised in neuroblastoma. Although not all RBPs appear suitable for drug design, or carry prognostic significance, we show that several RBPs have strong rationale for inhibition and mechanistic studies, representing an alternative, but nonetheless promising therapeutic strategy in neuroblastoma treatment. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

16 pages, 862 KiB  
Review
The Potential Contribution of Dysfunctional RNA-Binding Proteins to the Pathogenesis of Neurodegeneration in Multiple Sclerosis and Relevant Models
by Cole D. Libner, Hannah E. Salapa and Michael C. Levin
Int. J. Mol. Sci. 2020, 21(13), 4571; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134571 - 27 Jun 2020
Cited by 14 | Viewed by 3925
Abstract
Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms [...] Read more.
Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms of neurodegeneration in MS and its models, with a focus on RNA-binding protein dysfunction. Studying RNA-binding protein dysfunction addresses a gap in our understanding of the pathogenesis of MS, which will allow for novel therapies to be generated to attenuate neurodegeneration before irreversible central nervous system damage occurs. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

29 pages, 1535 KiB  
Review
RNA-Targeted Therapies and High-Throughput Screening Methods
by Siran Zhu, Saul Rooney and Gracjan Michlewski
Int. J. Mol. Sci. 2020, 21(8), 2996; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082996 - 23 Apr 2020
Cited by 18 | Viewed by 7164
Abstract
RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic [...] Read more.
RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic shift in the knowledge base, with RNA increasingly being recognised as an attractive target for precision medicine therapies. In this article, we are going to review current RNA-targeted therapies. Furthermore, we will scrutinise a range of drug discoveries targeting protein-RNA interactions. In particular, we will focus on the interplay between Lin28 and let-7, splicing regulatory proteins and survival motor neuron (SMN) pre-mRNA, as well as HuR, Musashi, proteins and their RNA targets. We will highlight the mechanisms RBPs utilise to modulate RNA metabolism and discuss current high-throughput screening strategies. This review provides evidence that we are entering a new era of RNA-targeted medicine. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

30 pages, 3492 KiB  
Review
From the Argonauts Mythological Sailors to the Argonautes RNA-Silencing Navigators: Their Emerging Roles in Human-Cell Pathologies
by Vasiliki I. Pantazopoulou, Stella Georgiou, Panos Kakoulidis, Stavroula N. Giannakopoulou, Sofia Tseleni, Dimitrios J. Stravopodis and Ema Anastasiadou
Int. J. Mol. Sci. 2020, 21(11), 4007; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114007 - 03 Jun 2020
Cited by 7 | Viewed by 4862
Abstract
Regulation of gene expression has emerged as a fundamental element of transcript homeostasis. Key effectors in this process are the Argonautes (AGOs), highly specialized RNA-binding proteins (RBPs) that form complexes, such as the RNA-Induced Silencing Complex (RISC). AGOs dictate post-transcriptional gene-silencing by directly [...] Read more.
Regulation of gene expression has emerged as a fundamental element of transcript homeostasis. Key effectors in this process are the Argonautes (AGOs), highly specialized RNA-binding proteins (RBPs) that form complexes, such as the RNA-Induced Silencing Complex (RISC). AGOs dictate post-transcriptional gene-silencing by directly loading small RNAs and repressing their mRNA targets through small RNA-sequence complementarity. The four human highly-conserved family-members (AGO1, AGO2, AGO3, and AGO4) demonstrate multi-faceted and versatile roles in transcriptome’s stability, plasticity, and functionality. The post-translational modifications of AGOs in critical amino acid residues, the nucleotide polymorphisms and mutations, and the deregulation of expression and interactions are tightly associated with aberrant activities, which are observed in a wide spectrum of pathologies. Through constantly accumulating information, the AGOs’ fundamental engagement in multiple human diseases has recently emerged. The present review examines new insights into AGO-driven pathology and AGO-deregulation patterns in a variety of diseases such as in viral infections and propagations, autoimmune diseases, cancers, metabolic deficiencies, neuronal disorders, and human infertility. Altogether, AGO seems to be a crucial contributor to pathogenesis and its targeting may serve as a novel and powerful therapeutic tool for the successful management of diverse human diseases in the clinic. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

12 pages, 2400 KiB  
Article
Quantitative Proteomics to Identify Nuclear RNA-Binding Proteins of Malat1
by Marian Scherer, Michal Levin, Falk Butter and Marion Scheibe
Int. J. Mol. Sci. 2020, 21(3), 1166; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031166 - 10 Feb 2020
Cited by 15 | Viewed by 4553
Abstract
The long non-coding RNA Malat1 has been implicated in several human cancers, while the mechanism of action is not completely understood. As RNAs in cells function together with RNA-binding proteins (RBPs), the composition of their RBP complex can shed light on their functionality. [...] Read more.
The long non-coding RNA Malat1 has been implicated in several human cancers, while the mechanism of action is not completely understood. As RNAs in cells function together with RNA-binding proteins (RBPs), the composition of their RBP complex can shed light on their functionality. We here performed quantitative interactomics of 14 non-overlapping fragments covering the full length of Malat1 to identify possible nuclear interacting proteins. Overall, we identified 35 candidates including 14 already known binders, which are able to interact with Malat1 in the nucleus. Furthermore, the use of fragments along the full-length RNA allowed us to reveal two hotspots for protein binding, one in the 5′-region and one in the 3′-region of Malat1. Our results provide confirmation on previous RNA-protein interaction studies and suggest new candidates for functional investigations. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

16 pages, 1533 KiB  
Review
The Emerging Role of the RNA-Binding Protein SFPQ in Neuronal Function and Neurodegeneration
by Yee Wa Lim, Dylan James, Jie Huang and Mihwa Lee
Int. J. Mol. Sci. 2020, 21(19), 7151; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197151 - 28 Sep 2020
Cited by 29 | Viewed by 6044
Abstract
RNA-binding proteins (RBPs) are a class of proteins known for their diverse roles in RNA biogenesis, from regulating transcriptional processes in the nucleus to facilitating translation in the cytoplasm. With higher demand for RNA metabolism in the nervous system, RBP misregulation has been [...] Read more.
RNA-binding proteins (RBPs) are a class of proteins known for their diverse roles in RNA biogenesis, from regulating transcriptional processes in the nucleus to facilitating translation in the cytoplasm. With higher demand for RNA metabolism in the nervous system, RBP misregulation has been linked to a wide range of neurological and neurodegenerative diseases. One of the emerging RBPs implicated in neuronal function and neurodegeneration is splicing factor proline- and glutamine-rich (SFPQ). SFPQ is a ubiquitous and abundant RBP that plays multiple regulatory roles in the nucleus such as paraspeckle formation, DNA damage repair, and various transcriptional regulation processes. An increasing number of studies have demonstrated the nuclear and also cytoplasmic roles of SFPQ in neurons, particularly in post-transcriptional regulation and RNA granule formation. Not surprisingly, the misregulation of SFPQ has been linked to pathological features shown by other neurodegenerative disease-associated RBPs such as aberrant RNA splicing, cytoplasmic mislocalization, and aggregation. In this review, we discuss recent findings on the roles of SFPQ with a particular focus on those in neuronal development and homeostasis as well as its implications in neurodegenerative diseases. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

24 pages, 4522 KiB  
Review
Dicing the Disease with Dicer: The Implications of Dicer Ribonuclease in Human Pathologies
by Eleni I. Theotoki, Vasiliki I. Pantazopoulou, Stella Georgiou, Panos Kakoulidis, Vicky Filippa, Dimitrios J. Stravopodis and Ema Anastasiadou
Int. J. Mol. Sci. 2020, 21(19), 7223; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197223 - 30 Sep 2020
Cited by 20 | Viewed by 5402
Abstract
Gene expression dictates fundamental cellular processes and its de-regulation leads to pathological conditions. A key contributor to the fine-tuning of gene expression is Dicer, an RNA-binding protein (RBPs) that forms complexes and affects transcription by acting at the post-transcriptional level via the targeting [...] Read more.
Gene expression dictates fundamental cellular processes and its de-regulation leads to pathological conditions. A key contributor to the fine-tuning of gene expression is Dicer, an RNA-binding protein (RBPs) that forms complexes and affects transcription by acting at the post-transcriptional level via the targeting of mRNAs by Dicer-produced small non-coding RNAs. This review aims to present the contribution of Dicer protein in a wide spectrum of human pathological conditions, including cancer, neurological, autoimmune, reproductive and cardiovascular diseases, as well as viral infections. Germline mutations of Dicer have been linked to Dicer1 syndrome, a rare genetic disorder that predisposes to the development of both benign and malignant tumors, but the exact correlation of Dicer protein expression within the different cancer types is unclear, and there are contradictions in the data. Downregulation of Dicer is related to Geographic atrophy (GA), a severe eye-disease that is a leading cause of blindness in industrialized countries, as well as to psychiatric and neurological diseases such as depression and Parkinson’s disease, respectively. Both loss and upregulation of Dicer protein expression is implicated in severe autoimmune disorders, including psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis and autoimmune thyroid diseases. Loss of Dicer contributes to cardiovascular diseases and causes defective germ cell differentiation and reproductive system abnormalities in both sexes. Dicer can also act as a strong antiviral with a crucial role in RNA-based antiviral immunity. In conclusion, Dicer is an essential enzyme for the maintenance of physiology due to its pivotal role in several cellular processes, and its loss or aberrant expression contributes to the development of severe human diseases. Further exploitation is required for the development of novel, more effective Dicer-based diagnostic and therapeutic strategies, with the goal of new clinical benefits and better quality of life for patients. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

29 pages, 2569 KiB  
Review
RNA-Binding Proteins in Acute Leukemias
by Konstantin Schuschel, Matthias Helwig, Stefan Hüttelmaier, Dirk Heckl, Jan-Henning Klusmann and Jessica I Hoell
Int. J. Mol. Sci. 2020, 21(10), 3409; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103409 - 12 May 2020
Cited by 31 | Viewed by 6298
Abstract
Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell [...] Read more.
Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

28 pages, 1203 KiB  
Review
RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma
by Jonas Weiße, Julia Rosemann, Vanessa Krauspe, Matthias Kappler, Alexander W. Eckert, Monika Haemmerle and Tony Gutschner
Int. J. Mol. Sci. 2020, 21(18), 6835; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186835 - 17 Sep 2020
Cited by 31 | Viewed by 6953
Abstract
Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target [...] Read more.
Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target RNAs, i.e., alternative splicing, polyadenylation, stability and turnover, localization, or translation as well as editing and chemical modification, thereby tuning gene expression programs of diverse cellular processes such as cell survival and malignant spread. Importantly, metastases are the major cause of cancer-associated deaths in general, and particularly in oral cancers, which account for 2% of the global cancer mortality. However, the roles and architecture of RBPs and RBP-controlled expression networks during the diverse steps of the metastatic cascade are only incompletely understood. In this review, we will offer a brief overview about RBPs and their general contribution to post-transcriptional regulation of gene expression. Subsequently, we will highlight selected examples of RBPs that have been shown to play a role in oral cancer cell migration, invasion, and metastasis. Last but not least, we will present targeting strategies that have been developed to interfere with the function of some of these RBPs. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

17 pages, 2724 KiB  
Article
RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma
by Markus Glaß, Patrick Michl and Stefan Hüttelmaier
Int. J. Mol. Sci. 2020, 21(11), 4190; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114190 - 11 Jun 2020
Cited by 16 | Viewed by 3105
Abstract
Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations [...] Read more.
Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations cannot explain the heterogeneity in therapeutic responses observed in PDAC patients, which limits efficiency of current therapeutic strategies. Instead, recent classifications of PDAC tumor samples are based on transcriptomics data and thus include information about epigenetic, transcriptomic, and post-transcriptomic deregulations. RNA binding proteins (RBPs) are important post-transcriptional regulators involved in every aspect of the RNA life cycle and thus considerably influence the transcriptome. In this study, we systematically investigated deregulated expression, prognostic value, and essentiality reported for RBPs in PDAC or PDAC cancer models using publicly available data. We identified 44 RBPs with suggested oncogenic potential. These include various proteins, e.g., IGF2 mRNA binding proteins (IGF2BPs), with reported tumor-promoting roles. We further characterized these RBPs and found common patterns regarding their expression, interaction, and regulation by microRNAs. These analyses suggest four prime candidate oncogenic RBPs with partially validated target potential: APOBEC1, IGF2BP1 and 3, and OASL. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

25 pages, 1108 KiB  
Review
Post-Transcriptional Expression Control in Platelet Biogenesis and Function
by Carolin T. Neu, Tony Gutschner and Monika Haemmerle
Int. J. Mol. Sci. 2020, 21(20), 7614; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207614 - 15 Oct 2020
Cited by 14 | Viewed by 3744
Abstract
Platelets are highly abundant cell fragments of the peripheral blood that originate from megakaryocytes. Beside their well-known role in wound healing and hemostasis, they are emerging mediators of the immune response and implicated in a variety of pathophysiological conditions including cancer. Despite their [...] Read more.
Platelets are highly abundant cell fragments of the peripheral blood that originate from megakaryocytes. Beside their well-known role in wound healing and hemostasis, they are emerging mediators of the immune response and implicated in a variety of pathophysiological conditions including cancer. Despite their anucleate nature, they harbor a diverse set of RNAs, which are subject to an active sorting mechanism from megakaryocytes into proplatelets and affect platelet biogenesis and function. However, sorting mechanisms are poorly understood, but RNA-binding proteins (RBPs) have been suggested to play a crucial role. Moreover, RBPs may regulate RNA translation and decay following platelet activation. In concert with other regulators, including microRNAs, long non-coding and circular RNAs, RBPs control multiple steps of the platelet life cycle. In this review, we will highlight the different RNA species within platelets and their impact on megakaryopoiesis, platelet biogenesis and platelet function. Additionally, we will focus on the currently known concepts of post-transcriptional control mechanisms important for RNA fate within platelets with a special emphasis on RBPs. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

22 pages, 518 KiB  
Review
RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer
by Katharina Jonas, George A. Calin and Martin Pichler
Int. J. Mol. Sci. 2020, 21(8), 2969; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082969 - 23 Apr 2020
Cited by 84 | Viewed by 7154
Abstract
The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of [...] Read more.
The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of numerous lncRNAs in cancer is known to contribute to virtually all hallmarks of cancer. An important regulatory mechanism of lncRNAs is the post-transcriptional regulation mediated by RNA-binding proteins (RBPs). So far, however, only a small number of known cancer-associated lncRNAs have been found to be regulated by the interaction with RBPs like human antigen R (HuR), ARE/poly(U)-binding/degradation factor 1 (AUF1), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and tristetraprolin (TTP). These RBPs regulate, by various means, two aspects in particular, namely the stability and the localization of lncRNAs. Importantly, these RBPs themselves are commonly deregulated in cancer and might thus play a major role in the deregulation of cancer-related lncRNAs. There are, however, still many open questions, for example regarding the context specificity of these regulatory mechanisms that, in part, is based on the synergistic or competitive interaction between different RBPs. There is also a lack of knowledge on how RBPs facilitate the transport of lncRNAs between different cellular compartments. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Figure 1

17 pages, 607 KiB  
Review
RNA-Binding Proteins in Pulmonary Hypertension
by Hui Zhang, R. Dale Brown, Kurt R. Stenmark and Cheng-Jun Hu
Int. J. Mol. Sci. 2020, 21(11), 3757; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113757 - 26 May 2020
Cited by 5 | Viewed by 2917
Abstract
Pulmonary hypertension (PH) is a life-threatening disease characterized by significant vascular remodeling and aberrant expression of genes involved in inflammation, apoptosis resistance, proliferation, and metabolism. Effective therapeutic strategies are limited, as mechanisms underlying PH pathophysiology, especially abnormal expression of genes, remain unclear. Most [...] Read more.
Pulmonary hypertension (PH) is a life-threatening disease characterized by significant vascular remodeling and aberrant expression of genes involved in inflammation, apoptosis resistance, proliferation, and metabolism. Effective therapeutic strategies are limited, as mechanisms underlying PH pathophysiology, especially abnormal expression of genes, remain unclear. Most PH studies on gene expression have focused on gene transcription. However, post-transcriptional alterations have been shown to play a critical role in inflammation and metabolic changes in diseases such as cancer and systemic cardiovascular diseases. In these diseases, RNA-binding proteins (RBPs) have been recognized as important regulators of aberrant gene expression via post-transcriptional regulation; however, their role in PH is less clear. Identifying RBPs in PH is of great importance to better understand PH pathophysiology and to identify new targets for PH treatment. In this manuscript, we review the current knowledge on the role of dysregulated RBPs in abnormal mRNA gene expression as well as aberrant non-coding RNA processing and expression (e.g., miRNAs) in PH. Full article
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
Show Figures

Graphical abstract

Back to TopTop