Wiley Interdisciplinary Reviews: RNA最新文献

MicroRNAs (miRNAs) are pivotal post-transcriptional regulators of gene networks in development and disease, with their functional output critically dependent on dynamic turnover. Dysregulation of miRNA turnover disrupts signaling fidelity and contributes to pathologies such as cancer and infection. This review synthesizes recent advances in understanding miRNA turnover, focusing on key degradation pathways-including ZSWIM8-mediated target-directed miRNA decay (TDMD), TUT4/7-DIS3L2-driven uridylation, and nuclease cleavage-and how they integrate with stability factors such as AGO association, terminal modifications, and sequence features to orchestrate global miRNA abundance and health status. From these insights, critical unresolved questions are delineated, such as identifying nucleases responsible for degrading TDMD-liberated miRNAs and elucidating compartment-specific degradation mechanisms in physiological contexts like the gut lumen and circulation. Addressing these questions will facilitate innovative strategies for targeting miRNA stability within precision medicine. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action.

Each time a eucaryotic cell divides, it replicates its DNA and packages the DNA into chormatin. Large amounts of all five histone proteins are co-ordinately synthesized to assemble the newly replicated chromatin. The metazoan replication-dependent (RD) histone mRNAs differ from all other cellular mRNAs. They are not polyadenylated, but end instead in a conserved stem-loop (SL). The genes encoding all five RD-histone mRNAs are clustered, and localized to a subdomain of the nucleus, the histone locus body (HLB). Factors required for transcription and 3' processing are concentrated in the HLB, allowing coordinate expression of the five histone mRNAs, which are synthesized inside the HLB. Since RD-histone genes lack introns, capping and 3' end formation are the only processing reactions required for their biosynthesis. A set of factors involved only in histone mRNA metabolism; NPAT, FLASH, U7 snRNP, and SLBP are required for synthesis of histone mRNAs. The HLB is present throughout the cell cycle. Histone mRNA expression is restricted to S-phase by phosphorylation of NPAT by cyclin E/cdk2. Like cleavage/polyadenylation, histone pre-mRNA processing requires recognition of a 5' signal, the SL, by SLBP, and a 3' signal, the histone downstream element (HDE) by U7 snRNP, with cleavage occurring between them. A subcomplex of CPSF, the cleavage module for cleavage/polyadenylation, is a component of the active U7 snRNP, which assembles in the HLB only in S-phase. CPSF73 catalyzes the cleavage of the nascent transcript to produce mature histone mRNA.

Alternative splicing (AS) is a fundamental mechanism that generates transcriptomic diversity by selectively including or excluding exons and introns from pre-mRNA transcripts, leading to the production of multiple protein isoforms from a single gene. This process plays a crucial role in cellular differentiation, tissue specificity, and response to environmental stimuli. Given that it enables organisms to adapt to varying conditions and maintain homeostasis, AS has become a pivotal area of study in molecular biology. The advancement of RNA-sequencing (RNA-seq) technologies has propelled the development of sophisticated tools designed to detect and analyze various AS events. These tools have become indispensable for researchers seeking to unravel the complexities of AS and its implications in health and disease. In this review, we delve into the prominent alternative splicing analysis tools rMATS, SUPPA2, LeafCutter, MISO, DEXSeq, MAJIQ, StringTie, and Cufflinks, discussing their strengths, limitations, and practical usability. Each of these tools offers unique functionalities tailored to different aspects of AS analysis, and their usefulness varies depending on computational requirements, ease of use, and the specificity of the AS events they detect. Through careful consideration of the functionalities and limitations of these tools, we offer insights into the biological contexts for which they might be best suited for AS analysis. This article is categorized under: RNA Methods > RNA Analyses In Vitro and In Silico RNA Processing > Splicing Regulation/Alternative Splicing.

Messenger ribonucleoprotein (mRNP) complexes assemble co-transcriptionally in the nucleus as RNA-binding proteins (RBPs) engage nascent transcripts. Ongoing RNA processing and RBP dynamics generate a diverse set of mRNPs, often producing a mature mRNA-capped, spliced, and polyadenylated-within a compact mRNP particle poised for nuclear export. The processing, packaging, and export of nuclear mRNPs are tightly regulated to ensure the fidelity of gene expression and to reprogram cellular function under changing organismal and environmental conditions. Understanding the compositional and organizational dynamics of nuclear mRNP assembly and maturation is essential, as dysregulation is linked to viral infections and a range of human diseases, including neurological disorders and cancer. Recent structural, biochemical, and in-cell studies have revealed key roles for the evolutionarily conserved Yra1/ALYREF proteins and the TRanscription-EXport (TREX) complex in mRNP packaging and export, highlighting broadly conserved functions across eukaryotes. While many questions remain, these advances have deepened our understanding of nuclear mRNA metabolism and offer new opportunities to investigate how disruptions in mRNA biogenesis and export factors, and their associated processes, contribute to disease. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Export and Localization > Nuclear Export/Import.

La and La-related proteins (LARPs) are conserved RNA-binding proteins that share a characteristic La motif (LaM) and have important functions in RNA metabolism. Members of the LARP1 family bind a cohort of mRNAs encoding factors involved in the process of mRNA translation, including ribosomal protein mRNAs (RP mRNAs). These mRNAs can contain a sequence of 5-15 pyrimidines in their 5'UTRs, immediately following the m⁷G cap, and are named 5' terminal oligopyrimidine (5'TOP) mRNAs. The DM15 domain of human LARP1 has been suggested to specifically recognize this motif, thereby affecting 5'TOP mRNA translation and stability. However, the specific function of LARP1 in this context remains unclear. Intriguingly, the 5'TOP motif is not found in RP mRNAs in C. elegans and yeast, while LARP1 orthologs in some systems lack the characteristic DM15 domain, suggesting that essential functions of LARP1 family members may precede the emergence of the 5'TOP motif and the DM15. In this work, we review studies in humans and several model organisms where we draw parallels between reported RNA binding modes and functions of different LARP1 orthologs. We further present common themes and areas for further investigation. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.

This article reviews the potential role of glycosylated RNA (glycoRNA), a new form of RNA epigenetic modification, in diseases. GlycoRNA has two types of modifications, N-glycosylation and O-glycosylation, and is widely present on the surface of many tissues and cells. Early studies have shown that glycoRNA can bind to molecules such as siglec receptors, P-selectin, and RNA-binding proteins (RBPs), thereby mediating intercellular interactions and participating in various pathological processes, including tumor proliferation and metastasis, as well as cardiovascular and cerebrovascular inflammatory responses and immune regulation. Although current research faces challenges such as unclear glycosylation mechanisms, limited detection techniques, and difficulties in clinical translation, glycoRNA still shows potential as a new biomarker and therapeutic target. Future research is expected to elucidate its molecular mechanisms further and promote its application in disease diagnosis and treatment. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease.

Eukaryotic gene expression is strictly controlled and regulated during translation. For eukaryotic mRNAs, canonical cap-dependent translation is the preferred pathway to synthesize proteins and starts with the recruitment of eukaryotic initation factors and the ribosome to the 5' m⁷G cap structure of the mRNA, followed by ribosome scanning and AUG recognition. Canonical translation can however be impaired during cellular responses to certain environmental factors, including stress, viral infection, and hypoxia. In response to these conditions, cells shut down the canonical translation initiation pathway and utilize alternative translation initiation mechanisms some of which are heavily dependent on RNA secondary structures. One such non-canonical initiation mechanism is mediated through Internal Ribosome Entry Sites (IRESs), found in viral and cellular mRNAs, which directly recruit the ribosome and do not require all translation initiation factors. Repeat-associated non-AUG (RAN) translation is another form of non-canonical translation initiation shown to heavily rely on RNA structure: this mode of translation initiation is relevant in the context of a subset of neurological diseases. This review focuses on the role of RNA structure in noncanonical translation initiation mechanisms, with a focus on IRES-mediated and RAN translation. This article is categorized under: Translation > Mechanisms Translation > Regulation RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry.

Cancer remains one of the leading causes of death worldwide. Despite various efforts to reduce cancer mortality, such as decreasing tobacco use, improving early detection and prevention methods, and enhancing cancer care and treatments, certain racial and ethnic groups continue to experience higher cancer incidence and mortality rates, along with shorter survival compared to other groups. Several factors, including socioeconomic status, environmental influences, diet, and behavior, contribute to these racial disparities. More importantly, scientists have identified a genetic basis for these observations, with a growing body of research highlighting microRNAs as significant players in cancer racial disparities. This review focuses on various types of microRNAs (such as epigenetically regulated, copy number altered, circulating, and exosomal) and microRNA single-nucleotide variations in the context of cancer-related racial disparities. Additionally, we have summarized the existing resources, including racial-specific model cell lines and cancer cohorts that include patients from diverse racial and ethnic backgrounds. Moreover, we provide here several key things to consider for future investigations. While many challenges remain, we aim to offer a balanced overview of this field to help scientists with varying expertise address these issues. This article is categorized under: RNA in Disease and Development > RNA in Disease.

Circular RNAs (circRNAs) are a class of noncoding RNAs characterized by covalently closed loop structures that confer high stability and diverse regulatory functions. Emerging evidence suggests that circRNAs modulate gene expression by acting as miRNA sponges, interacting with RNA-binding proteins (RBPs), influencing transcription, and serving as translational templates. Their dysregulation has been linked to various diseases, including cancer, cardiovascular, neurodegenerative, and metabolic disorders. Oxidative stress, a common hallmark in these pathologies, can alter circRNA expression and function. Natural antioxidants, derived from dietary sources such as fruits, vegetables, herbs, and medicinal plants, offer a promising approach for restoring redox homeostasis and influencing the regulation of circRNA networks. This review provides a comprehensive overview of how different classes of natural antioxidants, including flavonoids, polyphenols, carotenoids, terpenoids, vitamins, and alkaloids, modulate circRNA expression and function in various disease contexts. Representative compounds such as quercetin, curcumin, resveratrol, astaxanthin, kaempferol, and genistein exhibit circRNA-mediated actions that impact oxidative stress, inflammation, cell proliferation, apoptosis, and differentiation. The molecular mechanisms involve circRNA-miRNA-mRNA axes, interactions with RBPs, and modulation of epigenetic regulators and signaling pathways. We also discuss key challenges, including limited mechanistic understanding, bioavailability constraints, and the need for in vivo validation. Future perspectives emphasize the integration of antioxidant therapy with RNA-targeted approaches, advanced delivery systems, and personalized profiling of circRNA. Collectively, the regulatory interplay between natural antioxidants and circRNAs represents a promising frontier in redox biology and RNA-based therapeutics. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Small Molecule-RNA Interactions RNA in Disease and Development > RNA in Disease.

Biomolecular condensates are membraneless assemblies of proteins and nucleic acids, often formed through liquid-liquid phase separation. They selectively concentrate specific biomolecules and play essential roles in diverse cellular processes and diseases. This review discusses the emerging roles of biomolecular condensates in pre-mRNA 3' end processing, a critical step in mRNA biogenesis. 3' end processing factors are enriched in intrinsically disordered regions and undergo phase separation to form condensates that, in turn, fine-tune the efficiency and specificity of 3' end processing. Additionally, we describe how distinct 3' end processing pathways are spatially and functionally compartmentalized within nuclear biomolecular condensates, such as nuclear speckles and histone locus bodies. Finally, we propose that 3' end processing represents a promising experimental system to investigate fundamental principles underlying biomolecular condensate formation and function. 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.