Molecular Mechanisms of Myotonic Dystrophy: RNA-Mediated Pathogenesis and RNA-Binding Proteins

2018 ◽  
pp. 19-43
Author(s):  
Yoshihiro Kino ◽  
Jun-ichi Satoh ◽  
Shoichi Ishiura
Keyword(s):  
Myotonic Dystrophy ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins

The expanding world of metabolic enzymes moonlighting as RNA binding proteins

2021 ◽  
Author(s):  
Nicole J. Curtis ◽  
Constance J. Jeffery
Keyword(s):  
Gene Expression ◽  
Regulatory Networks ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Molecular Structures ◽  
Intermediary Metabolism ◽  
The Many ◽  
And Function

RNA binding proteins play key roles in many aspects of RNA metabolism and function, including splicing, transport, translation, localization, stability and degradation. Within the past few years, proteomics studies have identified dozens of enzymes in intermediary metabolism that bind to RNA. The wide occurrence and conservation of RNA binding ability across distant branches of the evolutionary tree suggest that these moonlighting enzymes are involved in connections between intermediary metabolism and gene expression that comprise far more extensive regulatory networks than previously thought. There are many outstanding questions about the molecular structures and mechanisms involved, the effects of these interactions on enzyme and RNA functions, and the factors that regulate the interactions. The effects on RNA function are likely to be wider than regulation of translation, and some enzyme–RNA interactions have been found to regulate the enzyme's catalytic activity. Several enzyme–RNA interactions have been shown to be affected by cellular factors that change under different intracellular and environmental conditions, including concentrations of substrates and cofactors. Understanding the molecular mechanisms involved in the interactions between the enzymes and RNA, the factors involved in regulation, and the effects of the enzyme–RNA interactions on both the enzyme and RNA functions will lead to a better understanding of the role of the many newly identified enzyme–RNA interactions in connecting intermediary metabolism and gene expression.

scholarly journals First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene

2020 ◽  
Vol 21 (20) ◽  
pp. 7803
Author(s):  
Julie Miro ◽  
Anne-Laure Bougé ◽  
Eva Murauer ◽  
Emmanuelle Beyne ◽  
Dylan Da Cunha ◽  
...  
Keyword(s):  
Large Scale ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Dystrophin Gene ◽  
Rna Seq ◽  
Spatio Temporal ◽  
Dmd Gene ◽  
Shed Light

The Duchenne muscular dystrophy (DMD) gene has a complex expression pattern regulated by multiple tissue-specific promoters and by alternative splicing (AS) of the resulting transcripts. Here, we used an RNAi-based approach coupled with DMD-targeted RNA-seq to identify RNA-binding proteins (RBPs) that regulate splicing of its skeletal muscle isoform (Dp427m) in a human muscular cell line. A total of 16 RBPs comprising the major regulators of muscle-specific splicing events were tested. We show that distinct combinations of RBPs maintain the correct inclusion in the Dp427m of exons that undergo spatio-temporal AS in other dystrophin isoforms. In particular, our findings revealed the complex networks of RBPs contributing to the splicing of the two short DMD exons 71 and 78, the inclusion of exon 78 in the adult Dp427m isoform being crucial for muscle function. Among the RBPs tested, QKI and DDX5/DDX17 proteins are important determinants of DMD exon inclusion. This is the first large-scale study to determine which RBP proteins act on the physiological splicing of the DMD gene. Our data shed light on molecular mechanisms contributing to the expression of the different dystrophin isoforms, which could be influenced by a change in the function or expression level of the identified RBPs.

scholarly journals Circular RNAs: Biogenesis, Mechanism, and Function in Human Cancers

2019 ◽  
Vol 20 (16) ◽  
pp. 3926 ◽  
Author(s):  
Xing Zhao ◽  
Yujie Cai ◽  
Jianzhen Xu
Keyword(s):  
Noncoding Rna ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cancer Development ◽  
Circular Rnas ◽  
Open Questions ◽  
Circular Configuration ◽  
And Function

CircRNAs are a class of noncoding RNA species with a circular configuration that is formed by either typical spliceosome-mediated or lariat-type splicing. The expression of circRNAs is usually abnormal in many cancers. Several circRNAs have been demonstrated to play important roles in carcinogenesis. In this review, we will first provide an introduction of circRNAs biogenesis, especially the regulation of circRNA by RNA-binding proteins, then we will focus on the recent findings of circRNA molecular mechanisms and functions in cancer development. Finally, some open questions are also discussed.

scholarly journals In heart failure reactivation of RNA-binding proteins drives the transcriptome into a fetal state

2021 ◽  
Author(s):  
Matteo D'Antonio ◽  
Jennifer P. Nguyen ◽  
Timothy D. Arthur ◽  
Hiroko Matsui ◽  
Margaret K.R. Donovan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Healthy Adult ◽  
Rna Binding Proteins ◽  
Expression Profiles ◽  
Fetal Tissue ◽  
Cellular Heterogeneity ◽  
Rna Seq

Transcriptome-wide expression changes occur during heart failure, including reactivation of fetal-specific isoforms. However, the underlying molecular mechanisms and the extent to which a fetal gene program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of alternative splicing differences (i.e. isoform switching) in cardiovascular system (CVS) tissues between fetal and adult (healthy and diseased) stages have included both cellular heterogeneity across bulk RNA-seq samples and limited availability of fetal tissue for research. To overcome these limitations, we have deconvoluted the cellular compositions of 996 RNA-seq samples representing heart failure, healthy adult (heart and arteria), and fetal-like (iPSC-derived cardiovascular progenitor cells) CVS tissues. Comparison of the expression profiles revealed that RNA-binding proteins (RBPs) are highly overexpressed in fetal-like compared with healthy adult and are reactivated in heart failure, which results in expression of thousands fetal-specific isoforms. Of note, isoforms for 20 different RBPs were among those that reverted in heart failure to the fetal-like expression pattern. We determined that, compared with adult-specific isoforms, fetal-specific isoforms are more likely to bind RBPs, have canonical sequences at their splice sites and encode proteins with more functions. Our findings suggest targeting RBP fetal-specific isoforms could result in novel therapeutics for heart failure.

scholarly journals Y-Box Binding Proteins in mRNP Assembly, Translation, and Stability Control

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 591 ◽  
Author(s):  
Daria Mordovkina ◽  
Dmitry N. Lyabin ◽  
Egor A. Smolin ◽  
Ekaterina M. Sogorina ◽  
Lev P. Ovchinnikov ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Large Family ◽  
Stability Control ◽  
Mrna Stabilization ◽  
Cell Tissue ◽  
Structural Peculiarities

Y-box binding proteins (YB proteins) are DNA/RNA-binding proteins belonging to a large family of proteins with the cold shock domain. Functionally, these proteins are known to be the most diverse, although the literature hardly offers any molecular mechanisms governing their activities in the cell, tissue, or the whole organism. This review describes the involvement of YB proteins in RNA-dependent processes, such as mRNA packaging into mRNPs, mRNA translation, and mRNA stabilization. In addition, recent data on the structural peculiarities of YB proteins underlying their interactions with nucleic acids are discussed.

scholarly journals The Combined Regulation of Long Non-coding RNA and RNA-Binding Proteins in Atherosclerosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Yuanyuan Ding ◽  
Ruihua Yin ◽  
Shuai Zhang ◽  
Qi Xiao ◽  
Hongqin Zhao ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Complex Disease ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Specific Interaction ◽  
Clinical Issue ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Long Non Coding Rna

Atherosclerosis is a complex disease closely related to the function of endothelial cells (ECs), monocytes/macrophages, and vascular smooth muscle cells (VSMCs). Despite a good understanding of the pathogenesis of atherosclerosis, the underlying molecular mechanisms are still only poorly understood. Therefore, atherosclerosis continues to be an important clinical issue worthy of further research. Recent evidence has shown that long non-coding RNAs (lncRNAs) and RNA-binding proteins (RBPs) can serve as important regulators of cellular function in atherosclerosis. Besides, several studies have shown that lncRNAs are partly dependent on the specific interaction with RBPs to exert their function. This review summarizes the important contributions of lncRNAs and RBPs in atherosclerosis and provides novel and comprehensible interaction models of lncRNAs and RBPs.

scholarly journals A novel Phytophthora sojae effector PsFYVE1 modulates transcription and alternative splicing of immunity related genes by targeting host RZ-1A protein

2021 ◽  
Author(s):  
Xinyu Lu ◽  
Zitong Yang ◽  
Wen Song ◽  
Jierui Si ◽  
Zhiyuan Yin ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Plant Immunity ◽  
Phytophthora Sojae ◽  
Protein Family ◽  
Plant Interactions ◽  
Fyve Domain

AbstractOomycete pathogens secrete many effectors to manipulate plant immunity and promote infection. However, relatively few effector types have been well characterized. In this study, members of a FYVE domain-containing protein family that is highly expanded in oomycetes were systematically identified, and one secreted protein, PsFYVE1, was selected for further study. PsFYVE1 enhanced Phytophthora infection in Nicotiana benthamiana and was necessary for P. sojae virulence. The FYVE domain of PsFYVE1 had PI3P-binding activity that depended on four conservative amino acid residues. Furthermore, PsFYVE1 targeted RNA-binding proteins RZ-1A/1B/1C in N. benthamiana and soybean, and silencing of NbRZ-1A/1B/1C genes attenuates plant immunity. NbRZ-1A was associated with spliceosome that included three important components, NbGRP7, NbGRP8, and NbU1-70K. Notably, PsFYVE1 could disrupt NbRZ-1A–NbGRP7 interaction. RNA-seq and subsequent experimental analysis demonstrated that PsFYVE1 and NbRZ-1A not only co-regulated transcription of NbHCT, NbEIN2, and NbSUS4 genes but also modulated pre-mRNA alternative splicing (AS) of the NbNSL1 gene, which participated in plant immunity. Collectively, these findings indicate that the FYVE domain-containing protein family includes potential new effector types and also highlight that plant pathogen effectors can regulate plant immunity related genes at both transcription and AS levels to promote disease.Author summaryMany plant pathogenic oomycetes secrete effector proteins into plants to facilitate infection. Discovering potential repertoire of novel effectors and corresponding molecular mechanisms are major themes in the study of oomycete–plant interactions. Here, we characterized a FYVE domain-containing protein (PsFYVE1) in P. sojae. PsFYVE1 carries a functional secretory signal peptide and is a virulence-essential effector for P. sojae infection. We demonstrated that PsFYVE1 interacted with a class of plant RNA-binding proteins, including soybean GmRZ-1A/1B/1C and N. benthamiana NbRZ-1A/1B/1C. Silencing of NbRZ-1A/1B/1C proteins increased Phytophthora infection and suppressed plant defense. Furthermore, NbRZ-1A interacted with the spliceosome components, and PsFYVE1 disrupted association between NbRZ-1A and spliceosome component NbGRP7. We examined the global transcription and alternative splicing (AS) changes regulated by PsFYVE1 and NbRZ-1A, which indicated that PsFYVE1 and NbRZ-1A co-regulated transcription and pre-mRNA AS of immunity-related genes. Thus, this study identifies a novel virulence-related effector from P. sojae and a class of positive regulators of plant immunity, and reveals a detailed mechanism of effector-medicated transcription and AS regulation during pathogen–plant interactions.

scholarly journals The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins

2021 ◽  
Author(s):  
Georg Petkau ◽  
Twm J Mitchell ◽  
Krishnendu Chakraborty ◽  
Sarah E Bell ◽  
Vanessa DAngeli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Influenza A ◽  
Cell Activation ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins

CD8 T cell differentiation into effector cells is initiated early after antigen encounter by signals from the T cell antigen receptor and costimulatory molecules. The molecular mechanisms that determine the timing and rate of differentiation however are not defined. Here we show that the RNA binding proteins (RBP) ZFP36 and ZFP36L1 limit the rate of differentiation of activated naive CD8 T cells and the potency of the resulting cytotoxic lymphocytes. The RBP act in an early and short temporal window to enforce dependency on costimulation via CD28 for full T cell activation and effector differentiation by directly binding mRNA of NF-kB, IRF8 and NOTCH1 transcription factors and IL2. Their absence in T cells, or the adoptive transfer of a small numbers of CD8 T cells lacking the RBP, promotes resilience to influenza A virus infection without immunopathology. These findings highlight ZFP36 and ZFP36L1 as nodes for the integration of the early T cell activation signals determining the speed and quality of the CD8 response.

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