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Cell Jun 2022Most circular RNAs are produced from the back-splicing of exons of precursor mRNAs. Recent technological advances have in part overcome problems with their circular... (Review)
Review
Most circular RNAs are produced from the back-splicing of exons of precursor mRNAs. Recent technological advances have in part overcome problems with their circular conformation and sequence overlap with linear cognate mRNAs, allowing a better understanding of their cellular roles. Depending on their localization and specific interactions with DNA, RNA, and proteins, circular RNAs can modulate transcription and splicing, regulate stability and translation of cytoplasmic mRNAs, interfere with signaling pathways, and serve as templates for translation in different biological and pathophysiological contexts. Emerging applications of RNA circles to interfere with cellular processes, modulate immune responses, and direct translation into proteins shed new light on biomedical research. In this review, we discuss approaches used in circular RNA studies and the current understanding of their regulatory roles and potential applications.
Topics: Proteins; RNA; RNA Precursors; RNA Splicing; RNA, Circular; RNA, Messenger
PubMed: 35584701
DOI: 10.1016/j.cell.2022.04.021 -
Nature Reviews. Genetics Mar 2023N-Methyladenosine (mA) is one of the most abundant modifications of the epitranscriptome and is found in cellular RNAs across all kingdoms of life. Advances in detection... (Review)
Review
N-Methyladenosine (mA) is one of the most abundant modifications of the epitranscriptome and is found in cellular RNAs across all kingdoms of life. Advances in detection and mapping methods have improved our understanding of the effects of mA on mRNA fate and ribosomal RNA function, and have uncovered novel functional roles in virtually every species of RNA. In this Review, we explore the latest studies revealing roles for mA-modified RNAs in chromatin architecture, transcriptional regulation and genome stability. We also summarize mA functions in biological processes such as stem-cell renewal and differentiation, brain function, immunity and cancer progression.
Topics: RNA; Methylation; RNA Processing, Post-Transcriptional; RNA, Messenger; Adenine
PubMed: 36261710
DOI: 10.1038/s41576-022-00534-0 -
Cell Aug 2023A system for programmable export of RNA molecules from living cells would enable both non-destructive monitoring of cell dynamics and engineering of cells capable of...
A system for programmable export of RNA molecules from living cells would enable both non-destructive monitoring of cell dynamics and engineering of cells capable of delivering executable RNA programs to other cells. We developed genetically encoded cellular RNA exporters, inspired by viruses, that efficiently package and secrete cargo RNA molecules from mammalian cells within protective nanoparticles. Exporting and sequencing RNA barcodes enabled non-destructive monitoring of cell population dynamics with clonal resolution. Further, by incorporating fusogens into the nanoparticles, we demonstrated the delivery, expression, and functional activity of exported mRNA in recipient cells. We term these systems COURIER (controlled output and uptake of RNA for interrogation, expression, and regulation). COURIER enables measurement of cell dynamics and establishes a foundation for hybrid cell and gene therapies based on cell-to-cell delivery of RNA.
Topics: Animals; Biological Transport; Mammals; RNA; RNA, Messenger; Viruses; Molecular Typing; Sequence Analysis, RNA; Cytological Techniques; Genetic Techniques
PubMed: 37437570
DOI: 10.1016/j.cell.2023.06.013 -
Molecular Cancer Jan 2022Metabolic reprogramming is one of the main characteristics of malignant tumors, which is due to the flexible changes of cell metabolism that can meet the needs of cell... (Review)
Review
Metabolic reprogramming is one of the main characteristics of malignant tumors, which is due to the flexible changes of cell metabolism that can meet the needs of cell growth and maintain the homeostasis of tissue environments. Cancer cells can obtain metabolic adaptation through a variety of endogenous and exogenous signaling pathways, which can not only promote the growth of malignant cancer cells, but also start the transformation process of cells to adapt to tumor microenvironment. Studies show that m6A RNA methylation is widely involved in the metabolic recombination of tumor cells. In eukaryotes, m6A methylation is the most abundant modification in mRNA, which is involved in almost all the RNA cycle stages, including regulation the transcription, maturation, translation, degradation and stability of mRNA. M6A RNA methylation can be involved in the regulation of physiological and pathological processes, including cancer. In this review, we discuss the role of m6A RNA methylation modification plays in tumor metabolism-related molecules and pathways, aiming to show the importance of targeting m6A in regulating tumor metabolism.
Topics: Adenosine; Animals; Biomarkers; Disease Management; Disease Susceptibility; Energy Metabolism; Gene Expression Regulation, Neoplastic; Humans; Methylation; Mitochondria; Neoplasms; RNA; RNA Processing, Post-Transcriptional; RNA, Circular; RNA, Messenger; RNA, Untranslated; Signal Transduction; Transcription Factors
PubMed: 35022030
DOI: 10.1186/s12943-022-01500-4 -
Nature Reviews. Drug Discovery Oct 2022RNA adopts 3D structures that confer varied functional roles in human biology and dysfunction in disease. Approaches to therapeutically target RNA structures with small... (Review)
Review
RNA adopts 3D structures that confer varied functional roles in human biology and dysfunction in disease. Approaches to therapeutically target RNA structures with small molecules are being actively pursued, aided by key advances in the field including the development of computational tools that predict evolutionarily conserved RNA structures, as well as strategies that expand mode of action and facilitate interactions with cellular machinery. Existing RNA-targeted small molecules use a range of mechanisms including directing splicing - by acting as molecular glues with cellular proteins (such as branaplam and the FDA-approved risdiplam), inhibition of translation of undruggable proteins and deactivation of functional structures in noncoding RNAs. Here, we describe strategies to identify, validate and optimize small molecules that target the functional transcriptome, laying out a roadmap to advance these agents into the next decade.
Topics: Humans; MicroRNAs; RNA; RNA Splicing; RNA, Long Noncoding; RNA, Untranslated
PubMed: 35941229
DOI: 10.1038/s41573-022-00521-4 -
Nature Biotechnology Feb 2023Circular RNAs (circRNAs) are stable and prevalent RNAs in eukaryotic cells that arise from back-splicing. Synthetic circRNAs and some endogenous circRNAs can encode...
Circular RNAs (circRNAs) are stable and prevalent RNAs in eukaryotic cells that arise from back-splicing. Synthetic circRNAs and some endogenous circRNAs can encode proteins, raising the promise of circRNA as a platform for gene expression. In this study, we developed a systematic approach for rapid assembly and testing of features that affect protein production from synthetic circRNAs. To maximize circRNA translation, we optimized five elements: vector topology, 5' and 3' untranslated regions, internal ribosome entry sites and synthetic aptamers recruiting translation initiation machinery. Together, these design principles improve circRNA protein yields by several hundred-fold, provide increased translation over messenger RNA in vitro, provide more durable translation in vivo and are generalizable across multiple transgenes.
Topics: RNA, Circular; RNA; RNA, Messenger; RNA Splicing
PubMed: 35851375
DOI: 10.1038/s41587-022-01393-0 -
Journal of Hematology & Oncology Jul 2020RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome... (Review)
Review
RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.
Topics: Alternative Splicing; Chromatin Assembly and Disassembly; DNA Damage; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Neoplasms; Polyadenylation; Protein Biosynthesis; Protein Processing, Post-Translational; RNA Processing, Post-Transcriptional; RNA Splicing; RNA Stability; RNA, Neoplasm; RNA, Untranslated; RNA-Binding Proteins; Subcellular Fractions; Transcription, Genetic
PubMed: 32653017
DOI: 10.1186/s13045-020-00927-w -
Cold Spring Harbor Perspectives in... Oct 20193' untranslated regions (3' UTRs) of messenger RNAs (mRNAs) are best known to regulate mRNA-based processes, such as mRNA localization, mRNA stability, and translation.... (Review)
Review
3' untranslated regions (3' UTRs) of messenger RNAs (mRNAs) are best known to regulate mRNA-based processes, such as mRNA localization, mRNA stability, and translation. In addition, 3' UTRs can establish 3' UTR-mediated protein-protein interactions (PPIs), and thus can transmit genetic information encoded in 3' UTRs to proteins. This function has been shown to regulate diverse protein features, including protein complex formation or posttranslational modifications, but is also expected to alter protein conformations. Therefore, 3' UTR-mediated information transfer can regulate protein features that are not encoded in the amino acid sequence. This review summarizes both 3' UTR functions-the regulation of mRNA and protein-based processes-and highlights how each 3' UTR function was discovered with a focus on experimental approaches used and the concepts that were learned. This review also discusses novel approaches to study 3' UTR functions in the future by taking advantage of recent advances in technology.
Topics: 3' Untranslated Regions; Protein Binding; Protein Biosynthesis; RNA Stability; RNA, Messenger; RNA-Binding Proteins
PubMed: 30181377
DOI: 10.1101/cshperspect.a034728 -
Nature Oct 2022RNA is a central and universal mediator of genetic information underlying the diversity of cell types and cell states, which together shape tissue organization and...
RNA is a central and universal mediator of genetic information underlying the diversity of cell types and cell states, which together shape tissue organization and organismal function across species and lifespans. Despite numerous advances in RNA sequencing technologies and the massive accumulation of transcriptome datasets across the life sciences, the dearth of technologies that use RNAs to observe and manipulate cell types remains a bottleneck in biology and medicine. Here we describe CellREADR (Cell access through RNA sensing by Endogenous ADAR), a programmable RNA-sensing technology that leverages RNA editing mediated by ADAR to couple the detection of cell-defining RNAs with the translation of effector proteins. Viral delivery of CellREADR conferred specific cell-type access in mouse and rat brains and in ex vivo human brain tissues. Furthermore, CellREADR enabled the recording and control of specific types of neurons in behaving mice. CellREADR thus highlights the potential for RNA-based monitoring and editing of animal cells in ways that are specific, versatile, simple and generalizable across organ systems and species, with wide applications in biology, biotechnology and programmable RNA medicine.
Topics: Animals; Humans; Mice; Rats; RNA; RNA Editing; Sequence Analysis, RNA; Transcriptome; Behavior, Animal; Brain; Neurons; Protein Biosynthesis
PubMed: 36198803
DOI: 10.1038/s41586-022-05280-1 -
British Journal of Cancer Aug 2023Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist... (Review)
Review
Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist on almost all RNAs. Roles of RNA modifications in cancer are garnering increasing interest. The research on mA RNA methylation in cancer is in full swing at present. However, there are still many other popular RNA modifications involved in the regulation of gene expression post-transcriptionally besides mA RNA methylation. In this review, we focus on several important RNA modifications including mA, mC, mG, 2'-O-Me, Ψ and A-to-I editing in cancer, which will provide a new perspective on tumourigenesis by peeking into the complex regulatory network of epigenetic RNA modifications, transcript processing, and protein translation.
Topics: Humans; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA; Neoplasms; Methylation
PubMed: 37095185
DOI: 10.1038/s41416-023-02275-1