Wiley Interdisciplinary Reviews: RNA最新文献

G-quadruplexes (G4s) are distinct nucleic acid secondary structures formed by guanine-rich sequences in both DNA and RNA. These structures readily form and fulfill diverse biological functions. The structural diversity of G4s is influenced by several factors, including their strand orientation, glycosidic bond angles, and loop configurations. G4s are widely distributed in functionally significant genomic regions, including telomeres, promoter regions, exons, 5' untranslated region (5' UTR), intron region, and 3' untranslated region (3' UTR). G4s are implicated in critical biological processes, including telomere elongation, DNA replication, DNA damage repair, transcription, translation, and epigenetic regulation. This overview offers a comprehensive analysis of the determinants of G4 structure and their impact on associated biological processes. Briefly, it describes the effects of G4s on cancers, viruses, and other pathogenic substances. This overview aims to contribute new ideas for the regulation of related mechanisms and their potential impact on the treatment strategies of related diseases. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems.

Transposable elements (TEs) have hijacked cellular machineries to replicate and spread throughout host genomes. TEs now make up a significant portion of eukaryotic genomes and play notable roles in genomic evolution, driving both speciation and providing raw material for genetic innovation. Barbara McClintock's pioneering work on these "jumping genes" laid the foundation for modern TE research; however, her paradigm-shifting theories in which TEs act as "controlling elements" were initially rejected due to the long-held belief that TEs were "junk" or parasitic DNA elements. Historically, the highly repetitive nature of TEs made it challenging to both identify and investigate functions. However, recent advances in genomics have greatly accelerated our understanding of TEs. Despite their potential to cause insertional mutagenesis and disease, many transposable elements have been co-opted by host genomes to contribute to gene regulation and development. In contrast to protein-coding genes that typically begin their journey as DNA, are transcribed into RNA, and reach their ultimate functional form as proteins, TEs can function as cis-regulatory DNA, functional RNA, and in rare cases, domesticated proteins and fusion events between TE and host genes. Driven by rapidly advancing technologies, the roles of TEs in both development and disease are being uncovered faster than ever, making current and future work an exciting continuation of Barbara McClintock's groundbreaking legacy.

The U1 small nuclear ribonucleoprotein (snRNP) complex is crucial for pre-mRNA splicing and the regulation of gene expression. As a core component of the spliceosome, it is responsible for recognizing 5'-splice sites and initiating the splicing process. Each subunit of this complex performs specific functions in the assembly and stabilization of the spliceosomal machinery. In addition to its classical role in splicing, the U1 snRNP complex is also involved in telescripting, a process that prevents premature polyadenylation. Dysregulation of U1 snRNP components has been associated with various disorders, including neurodegeneration, cancer, and autoimmune and eye diseases. Understanding the precise mechanisms of U1 snRNP complex dysregulation provides valuable insights into the molecular basis of these diseases, offering potential pathways for therapeutic intervention and prevention. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Mechanisms.

The neurofibromatosis type 1 (NF1) gene has 61 exons. The major alternative exon in NF1 pre-mRNA is exon 23a. Skipping and inclusion of this exon produce isoform I and isoform II neurofibromin, respectively. When the alternative exon was discovered in 1993, several experiments conducted in yeast and human cell lines quickly led to the conclusion that inclusion of this exon reduced the RasGAP function of the neurofibromin protein by 5-10-fold. Since then, research efforts on this seemingly important alternative splicing event have been sporadic, leaving many important questions unanswered, until after 2020 when several important papers related to the structure and function of exon 23a have been published. Two major advancements have been made. First, the cryo-EM structures of the full-length neurofibromin, of both isoforms, have been solved. More excitingly, the structure of isoform II neurofibromin that includes exon 23a provides important insight into why this isoform has reduced RasGAP activity. Second, the role of the altered splicing pattern of exon 23a in the development of high-grade glioma (HGG) has been investigated. In this review, we start with the introduction of alternative splicing of exon 23a, its discovery, differential expression patterns, and regulatory mechanisms that control this alternative splicing event. Next, we discuss the structural differences between the two isoforms which give insight into the differing RasGAP activities. We then review the in vivo biological function of the regulated inclusion of exon 23a, focusing on cognitive behaviors and brain tumor development. Finally, we briefly discuss the future directions of studies on NF1 exon 23a. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing.

mRNA translation is a highly orchestrated process that requires spatiotemporal control to ensure each protein is synthesized at the correct abundance, time, and location during human development and physiology. Classically, trans-acting RNA-binding proteins (RBPs) recognize cis-elements within mRNAs to provide one layer of gene-specific translational control. The function and properties of RBPs are diverse, with some harboring enzymatic capabilities, and can be multifaceted if present in larger RBP complexes. In this review, we focus on the role of Topoisomerase 3β (TOP3B) as a non-canonical RBP that is believed to influence the translation of select mRNAs and its connection with multiple human neurological disorders. Unlike any other encoded topoisomerase in the human genome, TOP3B is an mRNA-binding protein, catalytically favors RNA over DNA, and primarily localizes to the cytoplasm. Here we highlight important aspects of TOP3B as an RBP and raise multiple key questions for the field as a roadmap to better define its function in translational control and neuropathology. This article is categorized under: Translation > Regulation RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Voltage-gated calcium channels (VGCCs) are multi-subunit ion channel proteins that control and regulate a wide array of physiological processes. Their dysfunction has been implicated in several neurological, cardiac, psychiatric, endocrine, oncogenic, and muscular disorders. The diverse and specialized cellular functions involving VGCC-mediated calcium signaling stem from two primary mechanisms: differential and cell-specific expression of pore-forming (α1) and auxiliary subunit genes, and extensive alternative splicing of their pre-mRNA. All the 10 α1-encoding genes undergo alternative splicing to generate a wide array of cell-specific CaV variants with distinct biophysical, pharmacological, and protein-protein interaction properties. This proteomic diversity and the associated cell-specific expression signature of CaV splice variants are tightly regulated by trans-acting splicing factors-RNA-binding proteins that control the inclusion or skipping of alternatively spliced exons during post-transcriptional pre-mRNA processing. The discovery that several channelopathies are caused by aberrant splicing due to genetic mutations in either cis-acting binding elements on the pre-mRNA or in core splicing machinery components highlights the crucial role of alternative splicing in VGCC-related pathologies. These insights have opened new therapeutic avenues, as targeting the alternative splicing of disease-associated specific exons has recently emerged as a novel, promising treatment for neurodevelopmental disorders and channelopathies associated with splicing dysfunction.

3'-end cleavage and polyadenylation is an essential step of eukaryotic mRNA and lncRNA expression. The formation of a polyadenylation (polyA) site is determined by combinatory effects of multiple tandem motifs (~6 motifs in humans), each of which is bound by a protein subcomplex. However, motif occurrences and compositions are quite variable across individual polyA sites, leading to the technical challenge of quantifying polyadenylation activities and defining cleavage sites. Although conventional motif enrichment analyses and machine learning models identified contributing polyadenylation motifs, these cannot unbiasedly quantify motif crosstalk. Recently, several groups developed deep learning models to resolve sequence complexity, capture complex positional interactions among cis-regulatory motifs, examine polyA site formation, predict cleavage probability, and calculate site strength. These deep learning models have brought novel insights into polyadenylation biology, such as site configuration differences across species, cleavage heterogeneity, genomic parameters regulating site expression, and human genetic variants altering polyadenylation activities. In this review, we summarize the advances of deep learning models developed to address facets of polyadenylation regulation and discuss applications of the models.

RNA-binding proteins (RBPs) are a diverse class of proteins that interact with their target RNA molecules to regulate gene expression at the transcriptional and post-transcriptional levels. RBPs contribute to almost all aspects of RNA processing with sequence-specific, structure-specific, and nonspecific binding modes. Advances in our understanding of the mechanisms of RBP-mediated regulatory networks consisting of DNAs, RNAs, and protein complexes and the association between these networks and human diseases have been made very recently. Here, we discuss the "unconventional" functions of RBPs in transcriptional regulation by focusing on the cutting-edge investigations of chromatin-associated RBPs (ChRBPs). We briefly introduce examples of how ChRBPs influence the genomic features and molecular structures at the level of transcription. In addition, we focus on the post-transcriptional functions of various RBPs that regulate the biogenesis, transportation, stability control, and translation ability of circular RNA molecules (circRNAs). Lastly, we raise several questions about the clinical significance and potential therapeutic utility of disease-relevant RBPs.

Since the discovery of pseudouridine in the 1950s, the field of epitranscriptomics has expanded substantially, with over 330 RNA modifications now documented in the MODOMICS database. Among these, 2'-O-ribose methylation (2'-O-Me) is a prevalent modification characterized by the addition of a methyl group to the 2'-hydroxyl position of the ribose sugar, irrespective of the nucleotide bases. Initially detected in ribosomal RNA (rRNA), transfer RNA (tRNA), and messenger RNA (mRNA) in the 1970s, the methyltransferases responsible for 2'-O-Me were subsequently identified starting in the 1980s. Advancements in transcriptome-wide mapping techniques have since enabled precise identification of 2'-O-Me sites across various RNA species. Functional studies using knockdown or knockout models of specific 2'-O-Me methyltransferases have further elucidated their roles in different physiological processes. Notably, dysregulation of 2'-O-Me has been implicated in human diseases, including cancers and neurological disorders, underscoring its significance in controlling cellular homeostasis. This review covers the catalytic mechanisms and molecular functions of 2'-O-Me in different RNA species, discusses its physiological importance, and highlights the methods for transcriptome-wide mapping of this modification.

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.