Wiley Interdisciplinary Reviews: RNA最新文献

Eukaryotic gene expression is intricately regulated at multiple levels. The protein-coding genes are first transcribed as pre-mRNAs in the nucleus and undergo a series of RNA processing steps before being transported into the cytoplasm for translation. During RNA processing, most human genes (>95%) undergo alternative splicing to generate multiple mRNA isoforms from a single gene, which effectively diversifies the genome complexity. Since the splicing of most genes occurs co-transcriptionally, the regulation layers of gene expression often show functional interactions with each other. In this review, we provide a brief overview of alternative splicing regulation in three different layers (controlled by the splicing machinery, transcription process, and chromatin structure), emphasizing the regulatory roles of epigenetic modifications and the crosstalk between these layers. Specifically, we categorize the major effects of the epigenetic modifications on alternative splicing into three different types: by affecting transcription rate, splicing factor recruitment, or the expression/activity of splicing factor. The dysregulation of epigenetics and splicing are extremely common in cancer, we also discuss the potential mechanisms of how epigenetic changes can lead to splicing dysregulation and their functional consequences. We aim to provide insights into the complicated regulation of different gene expression layers, which will shed light on the novel approaches to modulate disease-related splicing dysregulation. This article is categorized under: RNA Processing > 3' End Processing RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease.

The budding yeast, Saccharomyces cerevisiae, has been used for decades as a powerful genetic tool to study a broad spectrum of biological topics. With its ease of use, economic utility, well-studied genome, and a highly conserved proteome across eukaryotes, it has become one of the most used model organisms. Due to these advantages, it has been used to study an array of complex human diseases. From broad, complex pathological conditions such as aging and neurodegenerative disease to newer uses such as SARS-CoV-2, yeast continues to offer new insights into how cellular processes are affected by disease and how affected pathways might be targeted in therapeutic settings. At the same time, the roles of RNA and RNA-based processes have become increasingly prominent in the pathology of many of these same human diseases, and yeast has been utilized to investigate these mechanisms, from aberrant RNA-binding proteins in amyotrophic lateral sclerosis to translation regulation in cancer. Here we review some of the important insights that yeast models have yielded into the molecular pathology of complex, RNA-based human diseases. This article is categorized under: RNA in Disease and Development > RNA in Disease.

Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N⁶ -methyladenosine (m⁶ A) is the most abundant modification in eukaryotic messenger RNA (mRNA) and has also been detected in non-coding RNAs, including long non-coding RNA, ribosomal RNA, and small nuclear RNA. In general, m⁶ A marks can alter RNA secondary structure and initiate unique RNA-protein interactions that can alter splicing, mRNA turnover, and translation, just to name a few. Although m⁶ A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m⁶ A marks have been established only recently. Thus far, there are four confirmed human methyltransferases that catalyze the transfer of a methyl group from S-adenosylmethionine (SAM) to the N⁶ position of adenosine, producing m⁶ A: methyltransferase-like protein (METTL) 3/METTL14 complex, METTL16, METTL5, and zinc-finger CCHC-domain-containing protein 4. Though the methyltransferases have unique RNA targets, all human m⁶ A RNA methyltransferases contain a Rossmann fold with a conserved SAM-binding pocket, suggesting that they utilize a similar catalytic mechanism for methyl transfer. For each of the human m⁶ A RNA methyltransferases, we present the biological functions and links to human disease, RNA targets, catalytic and kinetic mechanisms, and macromolecular structures. We also discuss m⁶ A marks in human viruses and parasites, assigning m⁶ A marks in the transcriptome to specific methyltransferases, small molecules targeting m⁶ A methyltransferases, and the enzymes responsible for hypermodified m⁶ A marks and their biological functions in humans. Understanding m⁶ A methyltransferases is a critical steppingstone toward establishing the m⁶ A epitranscriptome and more broadly the RNome. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

The RNA-binding Fox-1 homologue (Rbfox) proteins represent an ancient family of splicing factors, conserved through evolution. All members share an RNA recognition motif (RRM), and a particular affinity for the GCAUG signature in target RNA molecules. The role of Rbfox, as a splice factor, deciding the tissue-specific inclusion/exclusion of an exon, depending on its binding position on the flanking introns, is well known. Rbfox often acts in concert with other splicing factors, and forms splicing regulatory networks. Apart from this canonical role, recent studies show that Rbfox can also function as a transcription co-factor, and affects mRNA stability and translation. The repertoire of Rbfox targets is vast, including genes involved in the development of tissue lineages, such as neurogenesis, myogenesis, and erythropoeiesis, and molecular processes, including cytoskeletal dynamics, and calcium handling. A second layer of complexity is added by the fact that Rbfox expression itself is regulated by multiple mechanisms, and, in vertebrates, exhibits tissue-specific expression. The optimum dosage of Rbfox is critical, and its misexpression is etiological to various disease conditions. In this review, we discuss the contextual roles played by Rbfox as a tissue-specific regulator for the expression of many important genes with diverse functions, through the lens of the emerging data which highlights its involvement in many human diseases. Furthermore, we explore the mechanistic details provided by studies in model organisms, with emphasis on the work with Drosophila. This article is categorized under: RNA Processing > Splicing Mechanisms RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability RNA Processing > Splicing Regulation/Alternative Splicing.

Gastrointestinal (GI) cancer includes many cancer types, such as esophageal, liver, gastric, pancreatic, and colorectal cancer. As the cornerstone of personalized medicine for GI cancer, liquid biopsy based on noninvasive biomarkers provides promising opportunities for early diagnosis and dynamic treatment management. Recently, a growing number of studies have demonstrated the potential of cell-free RNA (cfRNA) as a new type of noninvasive biomarker in body fluids, such as blood, saliva, and urine. Meanwhile, transcriptomes based on high-throughput RNA detection technologies keep discovering new cfRNA biomarkers. In this review, we introduce the origins and applications of cfRNA, describe its detection and qualification methods in liquid biopsy, and summarize a comprehensive list of cfRNA biomarkers in different GI cancer types. Moreover, we also discuss perspective studies of cfRNA to overcome its current limitations in clinical applications. This article is categorized under: RNA in Disease and Development > RNA in Disease.

Ovarian cancer (OC) is the most common female cancer worldwide. Patients with OC have high mortality because of its complex and poorly understood pathogenesis. RNA epigenetic modifications, such as m⁶ A, m¹ A, and m⁵ C, are closely associated with the occurrence and development of OC. RNA modifications can affect the stability of mRNA transcripts, nuclear export of RNAs, translation efficiency, and decoding accuracy. However, there are few overviews that summarize the link between m⁶ A RNA modification and OC. Here, we discuss the molecular and cellular functions of different RNA modifications and how their regulation contributes to the pathogenesis of OC. By improving our understanding of the role of RNA modifications in the etiology of OC, we provide new perspectives for their use in OC diagnosis and treatment. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease.

The prevalence of ocular disorders is dramatically increasing worldwide, especially those that cause visual impairment and permanent loss of vision, including cataract, glaucoma, age-related macular degeneration, and diabetic retinopathy. Extensive evidence has shown that ncRNAs are key regulators in various biogenesis and biological functions, controlling gene expression related to histogenesis and cell differentiation in ocular tissues. Aberrant expression and function of ncRNA can lead to dysfunction of visual system and mediate progression of eye disorders. Here, we mainly offer an overview of the role of precise modulation of ncRNAs in eye development and function in patients with eye diseases. We also highlight the challenges and future perspectives in conducting ncRNA studies, focusing specifically on the role of ncRNAs that may hold expanded promise for their diagnostic and therapeutic applications in various eye diseases. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

Aminoacyl-tRNA synthetases form the protein family that controls the interpretation of the genetic code, with tRNA aminoacylation being the key chemical step during which an amino acid is assigned to a corresponding sequence of nucleic acids. In consequence, aminoacyl-tRNA synthetases have been studied in their physiological context, in disease states, and as tools for synthetic biology to enable the expansion of the genetic code. Here, we review the fundamentals of aminoacyl-tRNA synthetase biology and classification, with a focus on mammalian cytoplasmic enzymes. We compile evidence that the localization of aminoacyl-tRNA synthetases can be critical in health and disease. In addition, we discuss evidence from synthetic biology which made use of the importance of subcellular localization for efficient manipulation of the protein synthesis machinery. This article is categorized under: RNA Processing Translation > Translation Regulation RNA Processing > tRNA Processing RNA Export and Localization > RNA Localization.

Nucleic acid binding proteins regulate transcription, splicing, RNA stability, RNA localization, and translation, together tailoring gene expression in response to stimuli. Upon discovery, these proteins are typically classified as either DNA or RNA binding as defined by their in vivo functions; however, recent evidence suggests dual DNA and RNA binding by many of these proteins. High mobility group box (HMGB) proteins have a DNA binding HMGB domain, act as transcription factors and chromatin remodeling proteins, and are increasingly understood to interact with RNA as means to regulate gene expression. Herein, multiple layers of evidence that the HMGB family are dual DNA and RNA binding proteins is comprehensively reviewed. For example, HMGB proteins directly interact with RNA in vitro and in vivo, are localized to RNP granules involved in RNA processing, and their protein interactors are enriched in RNA binding proteins involved in RNA metabolism. Importantly, in cell-based systems, HMGB-RNA interactions facilitate protein-protein interactions, impact splicing outcomes, and modify HMGB protein genomic or cellular localization. Misregulation of these HMGB-RNA interactions are also likely involved in human disease. This review brings to light that as a family, HMGB proteins are likely to bind RNA which is essential to HMGB protein biology. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Translation accuracy is one of the most critical factors for protein synthesis. It is regulated by the ribosome and its dynamic behavior, along with translation factors that direct ribosome rearrangements to make translation a uniform process. Earlier structural studies of the ribosome complex with arrested translation factors laid the foundation for an understanding of ribosome dynamics and the translation process as such. Recent technological advances in time-resolved and ensemble cryo-EM have made it possible to study translation in real time at high resolution. These methods provided a detailed view of translation in bacteria for all three phases: initiation, elongation, and termination. In this review, we focus on translation factors (in some cases GTP activation) and their ability to monitor and respond to ribosome organization to enable efficient and accurate translation. This article is categorized under: Translation > Ribosome Structure/Function Translation > Mechanisms.