Wiley Interdisciplinary Reviews: RNA最新文献

During pre-mRNA splicing, introns are removed by the spliceosome, and the flanking exons are ligated to form mature mRNA, which is subsequently translated into protein. Traditionally, intronic RNAs have been regarded as "junk", presumed to be degraded for nucleotide turnover. Notably, after debranching, some linearized lariat RNAs can be further processed into snoRNAs, miRNAs, and other long non-coding RNAs. However, recent studies have shown that many intron-derived lariat RNAs can escape degradation and remain stable across various eukaryotic organisms, indicating they may play significant roles in cellular processes. Moreover, these naturally retained lariat RNAs are frequently observed in circular forms in vivo, suggesting that their linear tails are highly susceptible to degradation. This highlights lariat RNAs as an important source of circular RNAs. Furthermore, many lariat-derived circRNAs have been detected in the cytoplasm, implying active nuclear export and potential roles in cytoplasmic processes. In this review, we provide an overview of the life cycle of intron-derived lariat RNAs, focusing on their biogenesis, degradation, and retention. We also discuss the mechanisms that enable their resistance to degradation and the biological functions of stable lariat RNAs, shedding light on these seemingly "nonsense" yet inevitably produced non-coding intronic RNAs.

The heterogeneous nuclear ribonucleic acid protein family participates in various intracellular reactions, such as RNA splicing, transport, DNA repair, cellular signal transduction, and gene expression regulation, and is involved in various disease processes. As a late-discovered member, heterogeneous nuclear ribonucleoprotein A3 has received increasing attention, but its main physiological functions and exact mechanisms involved in disease processes have not yet reached a consensus. In this review, we summarize the function of heterogeneous nuclear ribonucleoprotein A3 and the literature on its role in neurodegenerative and metabolic diseases, as well as in various tumors, to explore the applicability of heterogeneous nuclear ribonucleoprotein A3 as a therapeutic target and prognostic indicator.

Epitranscriptomic modification of RNA is an important layer of regulation for gene expression. RNA modifications come in many flavors and generate a complex tapestry of a regulatory network. Here, we focus on two major RNA modifications, one on rRNA (2'O Methylation) and another on mRNA (N⁶-Methyladenosine [m⁶A]) and their impact on translation. The 2'O methyl group addition on the ribose sugar of rRNA plays a critical role in RNA folding, ribosome assembly, and its interaction with many RNA binding proteins. Differential methylation of these sites contributes to ribosome heterogeneity and generates potential "specialized ribosomes." Specialized ribosomes are proposed to play a variety of important roles in maintaining pluripotency, lineage specification, and compartmentalized and activity-mediated translation in neurons. The m⁶A modification, on the other hand, determines the stability, transport, and translation of subclasses of mRNA. The dynamic nature of m⁶A owing to the localization and activity of its writers, readers, and erasers makes it a powerful tool for spatiotemporal regulation of translation. While substantial information has accumulated on the nature and abundance of these modifications, their functional consequences are still understudied. In this article, we review the literature constructing the body of our understanding of these two modifications and their outcome on the regulation of translation in general and their impact on the nervous system in particular. We also explore the possibility of how these modifications may collaborate in modulating translation and provoke the thought to integrate the functions of multiple epitranscriptome modifications.

Coronaviruses utilize a positive-sense single-strand RNA, functioning simultaneously as mRNA and the genome. An RNA-dependent RNA polymerase (RdRP) plays a dual role in transcribing genes and replicating the genome, making RdRP a critical target in therapies against coronaviruses. This review explores recent advancements in understanding the coronavirus transcription machinery, discusses it within virus infection context, and incorporates kinetic considerations on RdRP activity. We also address steric limitations in coronavirus replication, particularly during early infection phases, and outline hypothesis regarding translation-transcription conflicts, postulating the existence of mechanisms that resolve these issues. In cells infected by coronaviruses, abundant structural proteins are synthesized from subgenomic RNA fragments (sgRNAs) produced via discontinuous transcription. During elongation, RdRP can skip large sections of the viral genome, resulting in the creation of shorter sgRNAs that reflects the stoichiometry of viral structural proteins. Although the precise mechanism of discontinuous transcription remains unknown, we discuss recent hypotheses involving long-distance RNA-RNA interactions, helicase-mediated RdRP backtracking, dissociation and reassociation of RdRP, and RdRP dimerization.

Life was originated from inorganic world and had experienced a long period of evolution in about 3.8 billion years. The time for emergence of the pioneer creations on Earth is debatable nowadays, and how the scenario for the prebiotic molecular interactions is still mysterious. Before the spreading of cellular organisms, chemical evolution was perhaps prevailing for millions of years, in which inorganic biosynthesis was ultimately replaced by biochemical reactions. Understanding the major molecular players and their interactions toward cellular life is fundamental for current medical science and extraterrestrial life exploration. In this review, we propose a road map for the primordial molecular evolution in early Earth, which probably occurred adjacent to hydrothermal vents with a strong gradient of organic molecules, temperature, and metal contents. Natural selection of the macromolecules with strong secondary structures and catalytic centers is associated with decreasing of overall entropy of the biopolymers. Our review may shed lights into the important selection of gene-coding RNA with secondary structures from large amounts of random biopolymers and formation of ancient ribosomes with biological machines supporting the basic life processes. Integration of the free environmental ribosomes by the early cellular life as symbiotic molecular machines is probably the earliest symbiosis on Earth.

Ribonuclease L is an endonuclease that is activated as part of the dsRNA-driven innate immune response. Active RNase L cleaves pathogenic RNAs as a way to eliminate infections. However, there are additional and unexpected ways that RNase L causes changes in the host that promote an immune response and contribute to its role in host defense. Central to these unconventional mechanisms is the observation that RNase L also degrades the mRNA of the host. In turn, mRNA fragments that RNase L generates can be translated. This causes activation of a ribosome collision sensor that leads to downstream signaling and cell death. Additionally, the liberation of RNA binding proteins after RNA decay appears to affect gene expression. In this review, we discuss these and other recent advances that focus on novel and unusual ways RNase L contributes to innate immunity.

Repeat expansion disorders (REDs) encompass over 50 inherited neurological disorders and are characterized by the expansion of short tandem nucleotide repeats beyond a specific repeat length. Particularly intriguing among these are multiple fragile X-associated disorders (FXds), which arise from an expansion of CGG repeats in the 5' untranslated region of the FMR1 gene. Despite arising from repeat expansions in the same gene, the clinical manifestations of FXds vary widely, encompassing developmental delays, parkinsonism, dementia, and an increased risk of infertility. FXds also exhibit molecular mechanisms observed in other REDs, that is, gene- and protein-loss-of-function and RNA- and protein-gain-of-function. The heterogeneity of phenotypes and pathomechanisms in FXds results from the different lengths of the CGG tract. As the number of repeats increases, the structures formed by RNA and DNA fragments containing CGG repeats change significantly, contributing to the diversity of FXd phenotypes and mechanisms. In this review, we discuss the role of RNA and DNA structures formed by expanded CGG repeats in driving FXd pathogenesis and how the genetic instability of CGG repeats is mediated by the complex interplay between transcription, DNA replication, and repair. We also discuss therapeutic strategies, including small molecules, antisense oligonucleotides, and CRISPR-Cas systems, that target toxic RNA and DNA involved in the development of FXds.

The RNA recognition motif (RRM) is the most common RNA binding domain found in the human proteome. RRM domains provide RNA-binding proteins with sequence specific RNA recognition allowing them to participate in RNA-centric processes such as mRNA maturation, translation initiation, splicing, and RNA degradation. They are drivers of various diseases through overexpression or mutation, making them attractive therapeutic targets and addressing these proteins through their RRM domains with chemical compounds is gaining ever more attention. However, it is still very challenging to find selective and potent RNA-competitors due to the small size of the domain and high structural conservation of its RNA binding interface. Despite these challenges, a selection of compounds has been reported for several RRM containing proteins, but often with limited biophysical evidence and low selectivity. A solution to selectively targeting RRM domains might be through avoiding the RNA-binding surface altogether, but rather look for composite pockets formed with other proteins or for protein-protein interaction sites that regulate the target's activity but are less conserved. Alternative modalities, such as oligonucleotides, peptides, and molecular glues, are exciting new approaches to address these challenging targets and achieve the goal of therapeutic intervention at the RNA regulatory level.

RNA processing involves steps such as capping, splicing, polyadenylation, modification, and nuclear export. These steps are essential for transforming genetic information in DNA into proteins and contribute to RNA diversity and complexity. Many biochemical methods have been developed to profile and quantify RNAs, as well as to identify the interactions between RNAs and RNA-binding proteins (RBPs), especially when coupled with high-throughput sequencing technologies. With the rapid accumulation of diverse data, it is crucial to develop computational methods to convert the big data into biological knowledge. In particular, machine learning and deep learning models are commonly utilized to learn the rules or codes governing the transformation from DNA sequences to intriguing RNAs based on manually designed or automatically extracted features. When precise enough, the RNA codes can be incredibly useful for predicting RNA products, decoding the molecular mechanisms, forecasting the impact of disease variants on RNA processing events, and identifying driver mutations. In this review, we systematically summarize the biochemical and computational methods for deciphering five important RNA codes related to alternative splicing, alternative polyadenylation, RNA localization, RNA modifications, and RBP binding. For each code, we review the main types of experimental methods used to generate training data, as well as the key features, strategic model structures, and advantages of representative tools. We also discuss the challenges encountered in developing predictive models using large language models and extensive domain knowledge. Additionally, we highlight useful resources and propose ways to improve computational tools for studying RNA codes.

All proteins in living organisms are produced in ribosomes that facilitate the translation of genetic information into a sequence of amino acid residues. During translation, the ribosome undergoes initiation, elongation, termination, and recycling. In fact, peptide bonds are formed only during the elongation phase, which comprises periodic association of transfer RNAs and multiple auxiliary proteins with the ribosome and the addition of an amino acid to the nascent polypeptide one at a time. The protein spends a considerable amount of time attached to the ribosome. Here, we conceptually divide this portion of the protein lifetime into three stages. We define each stage on the basis of the position of the N-terminus of the nascent polypeptide within the ribosome exit tunnel and the context of the catalytic center. We argue that nascent polypeptides experience a variety of forces that determine how they translocate through the tunnel and interact with the tunnel walls. We review current knowledge about nascent polypeptide translocation and identify several white spots in our understanding of the birth of proteins.