RNA modification: mechanisms and therapeutic targets

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Aug. 24, 2023

Abstract RNA modifications are dynamic and reversible chemical on substrate that regulated by specific modifying enzymes. They play important roles in the regulation of many biological processes various diseases, such as development cancer other diseases. With help advanced sequencing technologies, role has caught increasing attention human diseases scientific research. In this review, we briefly summarized basic mechanisms several common modifications, including m6A, m5C, m1A, m7G, Ψ, A-to-I editing ac4C. Importantly, discussed their potential functions cancer, neurological disorders, cardiovascular metabolic genetic developmental well immune disorders. Through “writing-erasing-reading” mechanisms, regulate stability, translation, localization pivotal disease-related mRNAs to manipulate disease development. Moreover, also highlighted review all currently available RNA-modifier-targeting small molecular inhibitors or activators, most which designed against m6A-related enzymes, METTL3, FTO ALKBH5. This provides clues for clinical therapy future study directions modification field. More in-depth studies further activators needed a thorough understanding epitranscriptomics diagnosis, treatment, prognosis

Language: Английский

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Chemically Modified Platforms for Better RNA Therapeutics

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(3), P. 929 - 1033

Published: Jan. 29, 2024

RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential disease prevention and treatment. However, despite their remarkable achievements, these encounter substantial challenges including low stability, susceptibility to degradation by nucleases, prominent negative charge, thereby hindering further development. Chemically modified platforms emerged as strategic innovation, focusing on precise alterations either RNA moieties or associated delivery vectors. This comprehensive review delves into platforms, underscoring significance augmenting performance translational prospects of therapeutics. It encompasses an in-depth analysis various chemically that been instrumental propelling therapeutics toward clinical utility. Moreover, scrutinizes rationale behind diverse chemical modification techniques aiming at optimizing therapeutic efficacy molecules, facilitating robust management. Recent empirical studies corroborating enhancement through modifications are highlighted. Conclusively, we offer profound insights transformative impact drugs delineates prospective trajectories for future development integration.

Language: Английский

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IL7 increases targeted lipid nanoparticle–mediated mRNA expression in T cells in vitro and in vivo by enhancing T cell protein translation

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(13)

Published: March 21, 2024

The use of lipid nanoparticles (LNP) to encapsulate and deliver mRNA has become an important therapeutic advance. In addition vaccines, LNP-mRNA can be used in many other applications. For example, targeting the LNP with anti-CD5 antibodies (CD5/tLNP) allow for efficient delivery payloads T cells express protein. As percentage protein expressing induced by intravenous injection CD5/tLNP is relatively low (4-20%), our goal was find ways increase mRNA-induced translation efficiency. We showed that cell activation using anti-CD3 antibody improved expression after transfection vitro but not vivo. health increased cytokines, therefore, mCherry as a reporter, we found culturing either mouse or human cytokine IL7 significantly delivered both CD4 + CD8 vitro. By pre-treating mice systemic followed tLNP administration, observed Transcriptomic analysis treated revealed enhanced genomic pathways associated translation. Improved translational ability demonstrated showing levels electroporation cultured presence IL7, IL2 IL15. These data show selectively increases cells, this property improve tLNP-delivered

Language: Английский

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RNA modification in cardiovascular disease: implications for therapeutic interventions

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 27, 2023

Abstract Cardiovascular disease (CVD) is the leading cause of death in world, with a high incidence and youth-oriented tendency. RNA modification ubiquitous indispensable cell, maintaining cell homeostasis function by dynamically regulating gene expression. Accumulating evidence has revealed role aberrant expression CVD caused dysregulated modification. In this review, we focus on nine common modifications: N 6 -methyladenosine (m A), 1 5-methylcytosine 5 C), 7 -methylguanosine G), 4 -acetylcytosine (ac pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) editing, modifications U34 tRNA wobble. We summarize key regulators their effects expression, such as splicing, maturation, transport, stability, translation. Then, based classification CVD, mechanisms which occurs progresses through are discussed. Potential therapeutic strategies, therapy, reviewed these mechanisms. Herein, some (such stroke peripheral vascular disease) not included due to limited availability literature. Finally, prospective applications challenges discussed for purpose facilitating clinical Moreover, look forward more studies exploring roles future, there substantial uncultivated areas be explored.

Language: Английский

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tRNA modifications: insights into their role in human cancers

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 33(12), P. 1035 - 1048

Published: May 12, 2023

Language: Английский

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Emerging Roles of RNA Methylation in Development

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(23), P. 3417 - 3427

Published: Nov. 15, 2023

More than 170 different types of chemical modifications have been identified on diverse RNA, collectively known as the epitranscriptome. Among them, N6-methyladenine (m6A), 5-methylcytosine (m5C), N1-methyladenine (m1A), and N7-methylguanosine (m7G) ubiquitous post-transcriptional modification are widely involved in regulating metabolic processes such RNA degradation, translation, stability, export, mediating important physiological pathological stress regulation, immune response, development, tumorigenesis. Recently, regulatory role during developmental is getting more attention. Therefore, development low-input even single-cell high-resolution sequencing technologies crucial for exploration roles these biological events trace samples.This account focuses various processes. We describe distribution characteristics modifications, catalytic enzymes, binding proteins, technologies. dynamically reversible, which can be catalyzed by methyltransferases eliminated demethylases. m6A most abundant eukaryote mRNA, mainly concentrated near stop codon, involves metabolism regulation. m5C, another studied modification, has a organisms species, enriched regions downstream translation initiation sites broadly distributes across whole coding sequence (CDS) mammalian mRNAs. m1A, with lower abundance m6A, distributed types, locates 5' untranslated region (5'UTR) mRNA regulates translation. m7G, one common eukaryotes, at cap internal positions RNAs recently gained considerable attention.Thanks to technology, found regulate tumorigenic process, including tumor proliferation, invasion, metastasis modulating oncogenes suppressor genes, affect oocyte maturation embryonic through maternal zygotic genes. m5C related proteins participate plant growth, neural stem cell differentiation dependent manner. m1A also revealed m7G dysregulation neurodevelopmental disorders neurodegenerative diseases.Collectively, we summarized gradually exhibited methylation discussed possibility candidate biomarkers potential therapeutic targets. The technological anticipated major driving force expand our knowledge this field.

Language: Английский

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Novel insight into RNA modifications in tumor immunity: Promising targets to prevent tumor immune escape

The Innovation, Journal Year: 2023, Volume and Issue: 4(4), P. 100452 - 100452

Published: May 29, 2023

•RNA modification is a novel hotspot of epigenetic research, affecting wide range physiological and pathological processes.•RNA plays an important role in tumor immunity.•RNA may be potential clinical therapeutic target to prevent immune escape. An immunosuppressive state typical feature the microenvironment. Despite dramatic success checkpoint inhibitor (ICI) therapy preventing cell escape from surveillance, primary acquired resistance have limited its use. Notably, recent trials shown that drugs can significantly improve outcome ICI various cancers, indicating importance modifications regulation tumors. Recently, RNA (N6-methyladenosine [m6A], N1-methyladenosine [m1A], 5-methylcytosine [m5C], etc.), areas been play crucial roles protumor antitumor immunity. In this review, we provide comprehensive understanding how m6A, m1A, m5C function immunity by directly regulating different cells as well indirectly through mechanisms, including modulating expression checkpoints, inducing metabolic reprogramming, secretion immune-related factors. Finally, discuss current status strategies targeting escape, highlighting their potential.

Language: Английский

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tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(4), P. 1146 - 1162

Published: Jan. 1, 2023

tRNA is one of the most conserved and abundant RNA species, which plays a key role during protein translation.tRNA molecules are post-transcriptionally modified by modifying enzymes.Since high-throughput sequencing technology has developed rapidly, modification types have been discovered in many research fields.In tRNA, numerous modifications enzymes implicated biological functions human diseases.In our review, we talk about relevant modifications, including stability, translation, cell cycle, oxidative stress, immunity.We also explore how contribute to progression diseases.Based on previous studies, discuss some emerging techniques for assessing aid discovering different modifications.

Language: Английский

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RNA modification-mediated mRNA translation regulation in liver cancer: mechanisms and clinical perspectives

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 21(4), P. 267 - 281

Published: Jan. 19, 2024

Language: Английский

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The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues

NAR Cancer, Journal Year: 2024, Volume and Issue: 6(1)

Published: Jan. 9, 2024

Abstract Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping landscape gene expression. This review explores how tRNA emerge as players, fine-tuning functionalities that not only maintain fidelity protein synthesis but also dictate expression and translation profiles. Highlighting their dysregulation a common denominator various cancers, we systematically investigate intersection both cytosolic mitochondrial with cancer biology. These impact key processes such cell proliferation, tumorigenesis, migration, metastasis, bioenergetics modulation tumor immune microenvironment. The recurrence altered modification patterns across different types underscores significance development, proposing them potential biomarkers actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine battle against cancer.

Language: Английский

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