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Nature Reviews. Molecular Cell Biology Oct 2019RNA methylation to form N-methyladenosine (mA) in mRNA accounts for the most abundant mRNA internal modification and has emerged as a widespread regulatory mechanism... (Review)
Review
RNA methylation to form N-methyladenosine (mA) in mRNA accounts for the most abundant mRNA internal modification and has emerged as a widespread regulatory mechanism that controls gene expression in diverse physiological processes. Transcriptome-wide mA mapping has revealed the distribution and pattern of mA in cellular RNAs, referred to as the epitranscriptome. These maps have revealed the specific mRNAs that are regulated by mA, providing mechanistic links connecting mA to cellular differentiation, cancer progression and other processes. The effects of mA on mRNA are mediated by an expanding list of mA readers and mA writer-complex components, as well as potential erasers that currently have unclear relevance to mA prevalence in the transcriptome. Here we review new and emerging methods to characterize and quantify the epitranscriptome, and we discuss new concepts - in some cases, controversies - regarding our understanding of the mechanisms and functions of mA readers, writers and erasers.
Topics: Adenosine; Animals; Gene Expression Regulation, Neoplastic; Humans; Methylation; Neoplasms; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Neoplasm
PubMed: 31520073
DOI: 10.1038/s41580-019-0168-5 -
Molecular Neurobiology Mar 2022N6-methyladenosine (m6A) is a dynamic reversible methylation modification of the adenosine N6 position and is the most common chemical epigenetic modification among mRNA... (Review)
Review
N6-methyladenosine (m6A) is a dynamic reversible methylation modification of the adenosine N6 position and is the most common chemical epigenetic modification among mRNA post-transcriptional modifications, including methylation, demethylation, and recognition. Post-transcriptional modification involves multiple protein molecules, including METTL3, METTL14, WTAP, KIAA1429, ALKBH5, YTHDF1/2/3, and YTHDC1/2. m6A-related proteins are expressed in almost all cells. However, the abnormal expression of m6A-related proteins may occur in the nervous system, thereby affecting neuritogenesis, brain volume, learning and memory, memory formation and consolidation, etc., and is implicated in the development of diseases, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, depression, epilepsy, and brain tumors. This review focuses on the functions of m6A in the development of central nervous system diseases, thus contributing to a deeper understanding of disease pathogenesis and providing potential clinical therapeutic targets for neurological diseases.
Topics: Adenosine; Epigenesis, Genetic; Methylation; Methyltransferases
PubMed: 35032318
DOI: 10.1007/s12035-022-02739-0 -
Nature Reviews. Genetics Feb 2021Following its transcription, RNA can be modified by >170 chemically distinct types of modifications - the epitranscriptome. In recent years, there have been substantial... (Review)
Review
Following its transcription, RNA can be modified by >170 chemically distinct types of modifications - the epitranscriptome. In recent years, there have been substantial efforts to uncover and characterize the modifications present on mRNA, motivated by the potential of such modifications to regulate mRNA fate and by discoveries and advances in our understanding of N -methyladenosine (mA). Here, we review our knowledge regarding the detection, distribution, abundance, biogenesis, functions and possible mechanisms of action of six of these modifications - pseudouridine (Ψ), 5-methylcytidine (mC), N -methyladenosine (mA), N -acetylcytidine (acC), ribose methylations (N) and N -methylguanosine (mG). We discuss the technical and analytical aspects that have led to inconsistent conclusions and controversies regarding the abundance and distribution of some of these modifications. We further highlight shared commonalities and important ways in which these modifications differ with respect to mA, based on which we speculate on their origin and their ability to acquire functions over evolutionary timescales.
Topics: Adenosine; Animals; Chromatography, Liquid; Evolution, Molecular; Genomics; High-Throughput Nucleotide Sequencing; Humans; Mass Spectrometry; RNA Processing, Post-Transcriptional; Transcriptome
PubMed: 33188361
DOI: 10.1038/s41576-020-00295-8 -
Annual Review of Cell and Developmental... Oct 2017In recent years, mA has emerged as an abundant and dynamically regulated modification throughout the transcriptome. Recent technological advances have enabled the... (Review)
Review
In recent years, mA has emerged as an abundant and dynamically regulated modification throughout the transcriptome. Recent technological advances have enabled the transcriptome-wide identification of mA residues, which in turn has provided important insights into the biology and regulation of this pervasive regulatory mark. Also central to our current understanding of mA are the discovery and characterization of mA readers, writers, and erasers. Over the last few years, studies into the function of these proteins have led to important discoveries about the regulation and function of mA. However, during this time our understanding of these proteins has also evolved considerably, sometimes leading to the reversal of early concepts regarding the reading, writing and erasing of mA. In this review, we summarize recent advances in mA research, and we highlight how these new findings have reshaped our understanding of how mA is regulated in the transcriptome.
Topics: Adenosine; Animals; DNA Methylation; Humans; RNA
PubMed: 28759256
DOI: 10.1146/annurev-cellbio-100616-060758 -
Cancer Cell Mar 2020N-Methyladenosine (mA) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible... (Review)
Review
N-Methyladenosine (mA) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification found not only in messenger RNAs but also in non-coding RNAs, mA affects the fate of the modified RNA molecules and plays important roles in almost all vital bioprocesses, including cancer development. Here we review the up-to-date knowledge of the pathological roles and underlying molecular mechanism of mA modifications (in both coding and non-coding RNAs) in cancer pathogenesis and drug response/resistance, and discuss the therapeutic potential of targeting mA regulators for cancer therapy.
Topics: Adenosine; Epigenesis, Genetic; Female; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Male; Mutation; Neoplasms; RNA, Messenger; RNA, Untranslated
PubMed: 32183948
DOI: 10.1016/j.ccell.2020.02.004 -
Nature Reviews. Clinical Oncology Aug 2023N-Methyladenosine (mA), the most prevalent internal modification in eukaryotic mRNA, has been extensively and increasingly studied over the past decade. Dysregulation of... (Review)
Review
N-Methyladenosine (mA), the most prevalent internal modification in eukaryotic mRNA, has been extensively and increasingly studied over the past decade. Dysregulation of RNA mA modification and its associated machinery, including writers, erasers and readers, is frequently observed in various cancer types, and the dysregulation profiles might serve as diagnostic, prognostic and/or predictive biomarkers. Dysregulated mA modifiers have been shown to function as oncoproteins or tumour suppressors with essential roles in cancer initiation, progression, metastasis, metabolism, therapy resistance and immune evasion as well as in cancer stem cell self-renewal and the tumour microenvironment, highlighting the therapeutic potential of targeting the dysregulated mA machinery for cancer treatment. In this Review, we discuss the mechanisms by which mA modifiers determine the fate of target RNAs and thereby influence protein expression, molecular pathways and cell phenotypes. We also describe the state-of-the-art methodologies for mapping global mA epitranscriptomes in cancer. We further summarize discoveries regarding the dysregulation of mA modifiers and modifications in cancer, their pathological roles, and the underlying molecular mechanisms. Finally, we discuss mA-related prognostic and predictive molecular biomarkers in cancer as well as the development of small-molecule inhibitors targeting oncogenic mA modifiers and their activity in preclinical models.
Topics: Humans; RNA; Adenosine; Neoplasms; RNA, Messenger; Biomarkers; Tumor Microenvironment
PubMed: 37221357
DOI: 10.1038/s41571-023-00774-x -
Biomedicine & Pharmacotherapy =... Apr 2019N6-methyladenosine (m6A), the most abundant internal modification of RNA in eukaryotic cells, has gained increasing attention in recent years. The m6A modification... (Review)
Review
N6-methyladenosine (m6A), the most abundant internal modification of RNA in eukaryotic cells, has gained increasing attention in recent years. The m6A modification affects multiple aspects of RNA metabolism, ranging from RNA processing, nuclear export, RNA translation to decay. Emerging evidence suggests that m6A methylation plays a critical role in cancer through various mechanisms. Moreover, m6A methylation has provided more possibilities for the early diagnosis and treatment of cancers. In this review, we focus on m6A-associated mechanisms and functions in several major malignancies and summarize the dual role of m6A methylation as well as its prospects in cancer.
Topics: Adenosine; Animals; Humans; Methylation; Neoplasms; RNA
PubMed: 30784918
DOI: 10.1016/j.biopha.2019.108613 -
Molecular Cancer Jan 2022N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic in... (Review)
Review
N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic in recent years. M6A plays multifunctional roles in normal and abnormal biological processes, and its role may vary greatly depending on the position of the m6A motif. Programmed cell death (PCD) includes apoptosis, autophagy, pyroptosis, necroptosis and ferroptosis, most of which involve the breakdown of the plasma membrane. Based on the implications of m6A methylation on PCD, the regulators and functional roles of m6A methylation were comprehensively studied and reported. In this review, we focus on the high-complexity links between m6A and different types of PCD pathways, which are then closely associated with the initiation, progression and resistance of cancer. Herein, clarifying the relationship between m6A and PCD is of great significance to provide novel strategies for cancer treatment, and has a great potential prospect of clinical application.
Topics: Adenosine; Apoptosis; Humans; Methylation; Neoplasms
PubMed: 35090469
DOI: 10.1186/s12943-022-01508-w -
Cell Research May 2018N-methyladenosine (mA), the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), has been shown to play critical roles in various normal... (Review)
Review
N-methyladenosine (mA), the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), has been shown to play critical roles in various normal bioprocesses such as tissue development, stem cell self-renewal and differentiation, heat shock or DNA damage response, and maternal-to-zygotic transition. The mA modification is deposited by the mA methyltransferase complex (MTC; i.e., writer) composed of METTL3, METTL14 and WTAP, and probably also VIRMA and RBM15, and can be removed by mA demethylases (i.e., erasers) such as FTO and ALKBH5. The fates of mA-modified mRNAs rely on the functions of distinct proteins that recognize them (i.e., readers), which may affect the stability, splicing, and/or translation of target mRNAs. Given the functional importance of the mA modification machinery in normal bioprocesses, it is not surprising that evidence is emerging that dysregulation of mA modification and the associated proteins also contributes to the initiation, progression, and drug response of cancers. In this review, we focus on recent advances in the study of biological functions and the underlying molecular mechanisms of dysregulated mA modification and the associated machinery in the pathogenesis and drug response of various types of cancers. In addition, we also discuss possible therapeutic interventions against the dysregulated mA machinery to treat cancers.
Topics: Adenosine; Carcinogenesis; Hematopoiesis; Humans; Neoplasms; RNA; Signal Transduction
PubMed: 29686311
DOI: 10.1038/s41422-018-0034-6 -
Journal of Drug Targeting 2015Adenosine is a naturally occurring purine nucleoside in every cell. Many critical treatments such as modulating irregular heartbeat (arrhythmias), regulation of central... (Review)
Review
Adenosine is a naturally occurring purine nucleoside in every cell. Many critical treatments such as modulating irregular heartbeat (arrhythmias), regulation of central nervous system (CNS) activity and inhibiting seizural episodes can be carried out using adenosine. Despite the significant potential therapeutic impact of adenosine and its derivatives, the severe side effects caused by their systemic administration have significantly limited their clinical use. In addition, due to adenosine's extremely short half-life in human blood (<10 s), there is an unmet need for sustained delivery systems to enhance efficacy and reduce side effects. In this article, various adenosine delivery techniques, including encapsulation into biodegradable polymers, cell-based delivery, implantable biomaterials and mechanical-based delivery systems, are critically reviewed and the existing challenges are highlighted.
Topics: Adenosine; Animals; Drug Delivery Systems; Drug Design; Half-Life; Humans; Polymers
PubMed: 26453156
DOI: 10.3109/1061186X.2015.1058803