Wiley Interdisciplinary Reviews: RNA最新文献

In recent years, there has been a growing appreciation for how regulatory events that occur either co- or post-transcriptionally contribute to the control of gene expression. Messenger RNAs (mRNAs) are extensively regulated throughout their metabolism in a precise spatiotemporal manner that requires sophisticated molecular mechanisms for cell-type-specific gene expression, which dictates cell function. Moreover, dysfunction at any of these steps can result in a variety of human diseases, including cancers, muscular atrophies, and neurological diseases. This review summarizes the steps of the central dogma of molecular biology, focusing on the post-transcriptional regulation of gene expression.

Aging is a progressive weakening of numerous functions of organisms resulting in diminished abilities to safeguard against environmental damage and augment physiological harmony. It is not a disease in itself; however, it is a main cause of debilitating and life-threatening chronic aging-related diseases (ARDs). tRNA-derived fragments (tDRs) are stable forms of tRNAs of 14-35 nt in length that function as regulatory small-RNA molecules. Here we aimed to perform a systematic review of original articles on the involvement of tDRs in the etiology of ARDs: their identification and characterization. The systematic review was conducted according to the Cochrane Handbook guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Based on the eligibility criteria defined for the study, 21 original articles were included in this systematic review, covering 11 ARDs. The preferred research method used to study tDRs was high-throughput sequencing combined with RT-qPCR, and as a result, a number of tDRs were implicated in ARDs. Importantly, an in-depth analysis of the articles allowed us to identify several shortcomings: (i) the tDRs nomenclature varies between studies and articles, making it often difficult to precisely identify molecules differentiating in a given disease; (ii) the chosen tDRs have all been studied for a miRNA-like mechanism of action; however, tDRs also function in RNAi-independent ways, which need to be studied as well; (iii) to precisely identify tDRs, the sequencing techniques that overcome the issues of modifications harbored by tRNAs must be used.

Adenosine-to-inosine (A-to-I) RNA editing is a key post-transcriptional modification that influences gene expression and various cellular processes. Advances in sequencing technologies have greatly contributed to the identification of A-to-I editing sites, providing insights into their distribution across coding and non-coding regions. These developments have facilitated the discovery of functionally relevant editing events and have advanced the understanding of their biological roles. This review presents the evolution of methodologies for RNA editing detection and examines recent advances, including chemically-assisted, enzyme-assisted, and quantitative approaches. By evaluating these techniques, we aim to help researchers select the most effective tools for investigating RNA editing and its broader implications in health and disease.

MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs found in eukaryotes with post-transcriptional regulatory functions. A variety of miRNAs is differentially expressed in cancer tissues and thus can be used as biomarkers. microRNA-135b-5p (miR-135b) has been shown to be involved in the pathological processes of a variety of neoplastic and non-neoplastic diseases. Under different conditions, miR-135b has different tumor suppressive and carcinogenic effects. miR-135b regulates the development of cancer, including metabolism, proliferation, apoptosis, invasion, fibrosis, angiogenesis, immunomodulation, and drug resistance. miR-135b can be used as a new biomarker for tumor diagnosis and prognosis, which has the potential for clinical guidance. This article reviews the relevant research on miR-135B in the field of tumors, including the biogenesis background of miR-135b, the expression of miR-135b in tumors, and the related targets and signaling pathways of miR-135b mediating tumor progression in order to sort out and explore the clinical transformation value of miR-135b.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by imbalanced immunity, vasculopathy, and excessive fibrosis. The etiology and pathology of this disease remain to be fully elucidated. Genetic predisposition, along with epigenetic modifications are widely considered to significantly affect its development. Among the components of epigenetics, non-coding RNAs (ncRNAs), comprising various types such as microRNA, long ncRNA, circular RNA, and others, play a crucial role. These ncRNAs perform several functions in the development of SSc and can potentially be employed as new targets for its diagnosis and treatment. This review discusses the roles of ncRNAs in the three primary pathological hallmarks-vasculopathy, imbalanced immunity, and excessive fibrosis-of SSc and highlights research progress in the role of RNAs in translational medicine against SSc. The review also provides a comprehensive outline of the key function of ncRNAs in SSc.

GEMIN5 is a predominantly cytoplasmic protein, initially identified as a member of the survival of motor neurons (SMN) complex. In addition, this abundant protein modulates diverse aspects of RNA-dependent processes, executing its functions through the formation of multi-component complexes. The modular organization of structural domains present in GEMIN5 enables this protein to perform various functions through its interaction with distinct partners. The protein is responsible for the recognition of small nuclear (sn)RNAs through its N-terminal region, and therefore for snRNP assembly. Beyond its role in spliceosome assembly, GEMIN5 regulates translation through the interaction with either RNAs or proteins. In the central region, a robust dimerization domain acts as a hub for protein-protein interaction, while a non-canonical RNA-binding site is located towards the C-terminus. Interestingly, GEMIN5 regulates the partitioning of mRNAs into polysomes, likely due to its RNA-binding capacity and its ability to bind native ribosomes. Understanding the functional and structural organization of the protein has brought an increasing interest in the last years with important implications in human disease. Patients carrying GEMIN5 biallelic variants suffer from neurodevelopmental delay, hypotonia, and cerebellar ataxia. This review discusses recent relevant works aimed at understanding the molecular mechanisms of GEMIN5 activity in gene expression, and also the challenges to discover new functions.

PIWI-interacting RNAs (piRNAs) are small non-coding RNA molecules that were originally described as responsible for binding to PIWI proteins to silence transposons in the germline genome. Here we discuss their controversial influence in regulating gene expression in human somatic cells. Although their functions in human somatic cells remain controversial, current research has focused on their potential contribution to human diseases including cancers and cardiovascular diseases (CVDs). These small RNA molecules directly interact with PIWI proteins to form piRNA-induced silencing complexes (piRISC). These complexes regulate not only long non-coding RNAs (lncRNAs) but also mRNAs in their 3' untranslated region. The controversy in human somatic cells occurs because not all of the reports demonstrate a direct interaction between the small non-coding RNAs and the PIWI proteins and also whether these established complexes have silencing activities. Therefore, their importance in human physiology and pathology continues to remain controversial. Here we discuss the challenges and limitations that need to be addressed in order to establish and harness the potential of these ncRNAs in potential clinical applications. In this review, we distinguish those examples that have been shown to function as silencing complexes (piRNAs) from those that appear to be silencing complexes based only on their ability to bind to PIWI proteins (piRNA-like) in human somatic cells.

Stress granules (SGs) are membrane-less organelles forming in the cytoplasm in response to various types of stress, including viral infection. SGs and SG-associated proteins can play either a proviral role, by facilitating viral replication, or an antiviral role, by limiting the translation capacity, sequestering viral RNA, or contributing to the innate immune response of the cell. Consequently, viruses frequently target stress granules while counteracting cellular translation shut-off and the antiviral response. One strategy is to sequester SG components, not only to impair their assembly but also to repurpose and incorporate them into viral replication sites. G3BP1 is a key SG protein, driving its nucleation through protein-protein and protein-RNA interactions. Many cellular proteins, including other SG components, interact with G3BP1 via their ΦxFG motifs. Notably, SARS-CoV N proteins and alphaviral nsP3 proteins contain similar motifs, allowing them to compete for G3BP1. Several SG proteins have been shown to interact with the flaviviral capsid protein, which is primarily responsible for anchoring the viral genome inside the virion. There are also numerous examples of structured elements within coronaviral and flaviviral RNAs recruiting or sponging SG proteins. Despite these insights, the structural and biochemical details of SG-virus interactions remain largely unexplored and are known only for a handful of cases. Exploring their molecular relevance for infection and discovering new examples of direct SG-virus contacts is highly important, as advances in this area will open new possibilities for the design of targeted therapies and potentially broad-spectrum antivirals.

Transfer RNA (tRNA) is not merely a passive carrier of amino acids, but an active regulator of mRNA translation controlling codon bias and optimality. The synthesis of various tRNA modifications is regulated by many "writer" enzymes, which utilize substrates from metabolic pathways or dietary sources. Metabolic and bioenergetic pathways, such as one-carbon (1C) metabolism and the tricarboxylic acid (TCA) cycle produce essential substrates for tRNA modifications synthesis, such as S-Adenosyl methionine (SAM), sulfur species, and α-ketoglutarate (α-KG). The activity of these metabolic pathways can directly impact codon decoding and translation via regulating tRNA modifications levels. In this review, we discuss the complex interactions between diet, metabolism, tRNA modifications, and mRNA translation. We discuss how nutrient availability, bioenergetics, and intermediates of metabolic pathways, modulate the tRNA modification landscape to fine-tune protein synthesis. Moreover, we highlight how dysregulation of these metabolic-tRNA interactions contributes to disease pathogenesis, including cancer, metabolic disorders, and neurodegenerative diseases. We also discuss the new emerging field of GlycoRNA biology drawing parallels from glycobiology and metabolic diseases to guide future directions in this area. Throughout our discussion, we highlight the links between specific modifications, their metabolic/dietary precursors, and various diseases, emphasizing the importance of a metabolism-centric tRNA view in understanding many pathologies. Future research should focus on uncovering the interplay between metabolism and tRNA in specific cellular and disease contexts. Addressing these gaps will guide new research into novel disease interventions.

Assemblysomes are recently discovered intracellular RNA-protein complexes that play important roles in cellular stress response, regulation of gene expression, and also in co-translational protein assembly. In this review, a wide spectrum overview of assemblysomes is provided, including their discovery, mechanism of action, characteristics, and potential applications in several fields. Assemblysomes are distinct liquid-liquid phase-separated condensates; they have certain unique properties differentiating them from other cellular granules. They are composed of ribosome-nascent protein chain complexes and are resistant to cycloheximide and EDTA. The discovery and observation of intracellular condensates, like assemblysomes, have further expanded our knowledge of cellular stress response mechanisms, particularly in DNA repair processes and defense against proteotoxicity. Ribosome profiling experiments and next-generation sequencing of cDNA libraries extracted from EDTA-resistant pellets-of ultracentrifuged cell lysates-have shed light on the composition and dynamics of assemblysomes, revealing their role as repositories for pre-made stress-responsive ribosome-nascent chain complexes. This review gives an exploration of assemblysomes' potential clinical applications from multiple aspects, including their usefulness as diagnostic biomarkers for chemotherapy resistance and their implications in cancer therapy. In addition, in this overview, we raise some theoretical ideas of industrial and agricultural applications connected to these membraneless organelles. However, we see several challenges. On one hand, we need to understand the complexity of assemblysomes' multiple functions and regulations; on the other hand, it is essential to bridge the gap between fundamental research and practical applications. Overall, assemblysome research can be perceived as a promising upcomer in the improvement of biomedical settings as well as those connected to agricultural and industrial aspects.