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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 -
Nucleic Acids Research Jul 2021Gene expression is regulated at many levels including co- or post-transcriptionally, where chemical modifications are added to RNA on riboses and bases. Expression... (Review)
Review
Gene expression is regulated at many levels including co- or post-transcriptionally, where chemical modifications are added to RNA on riboses and bases. Expression control via RNA modifications has been termed 'epitranscriptomics' to keep with the related 'epigenomics' for DNA modification. One such RNA modification is the N6-methylation found on adenosine (m6A) and 2'-O-methyladenosine (m6Am) in most types of RNA. The N6-methylation can affect the fold, stability, degradation and cellular interaction(s) of the modified RNA, implicating it in processes such as splicing, translation, export and decay. The multiple roles played by this modification explains why m6A misregulation is connected to multiple human cancers. The m6A/m6Am writer enzymes are RNA methyltransferases (MTases). Structures are available for functionally characterized m6A RNA MTases from human (m6A mRNA, m6A snRNA, m6A rRNA and m6Am mRNA MTases), zebrafish (m6Am mRNA MTase) and bacteria (m6A rRNA MTase). For each of these MTases, we describe their overall domain organization, the active site architecture and the substrate binding. We identify areas that remain to be investigated, propose yet unexplored routes for structural characterization of MTase:substrate complexes, and highlight common structural elements that should be described for future m6A/m6Am RNA MTase structures.
Topics: Adenosine; Animals; Bacteria; Humans; Methyltransferases; Zebrafish Proteins
PubMed: 34023900
DOI: 10.1093/nar/gkab378 -
Molecular Cancer Dec 2019N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating... (Review)
Review
N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.
Topics: Adenosine; Animals; Biomarkers; Disease Susceptibility; Gene Expression Regulation, Neoplastic; Humans; Methylation; Molecular Targeted Therapy; Neoplasms; Protein Binding; RNA, Messenger; Signal Transduction
PubMed: 31801551
DOI: 10.1186/s12943-019-1109-9 -
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 -
Molecular Cancer May 2020N6-methyladenosine (m6A) is considered the most common, abundant, and conserved internal transcript modification, especially in eukaryotic messenger RNA (mRNA). m6A is... (Review)
Review
N6-methyladenosine (m6A) is considered the most common, abundant, and conserved internal transcript modification, especially in eukaryotic messenger RNA (mRNA). m6A is installed by m6A methyltransferases (METTL3/14, WTAP, RBM15/15B, VIRMA and ZC3H13, termed "writers"), removed by demethylases (FTO, ALKBH5, and ALKBH3, termed "erasers"), and recognized by m6A-binding proteins (YTHDC1/2, YTHDF1/2/3, IGF2BP1/2/3, HNRNP, and eIF3, termed "readers"). Accumulating evidence suggests that m6A RNA methylation greatly impacts RNA metabolism and is involved in the pathogenesis of many kinds of diseases, including cancers. In this review, we focus on the physiological functions of m6A modification and its related regulators, as well as on the potential biological roles of these elements in human tumors.
Topics: Adenosine; Animals; Biomarkers, Tumor; DNA Methylation; Disease Progression; Epigenesis, Genetic; Humans; Methyltransferases; Neoplasms
PubMed: 32398132
DOI: 10.1186/s12943-020-01204-7 -
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 -
The EMBO Journal Feb 2021RNA carries a diverse array of chemical modifications that play important roles in the regulation of gene expression. N -methyladenosine (m A), installed onto mRNA by... (Review)
Review
RNA carries a diverse array of chemical modifications that play important roles in the regulation of gene expression. N -methyladenosine (m A), installed onto mRNA by the METTL3/METTL14 methyltransferase complex, is the most prevalent mRNA modification. m A methylation regulates gene expression by influencing numerous aspects of mRNA metabolism, including pre-mRNA processing, nuclear export, decay, and translation. The importance of m A methylation as a mode of post-transcriptional gene expression regulation is evident in the crucial roles m A-mediated gene regulation plays in numerous physiological and pathophysiological processes. Here, we review current knowledge on the mechanisms by which m A exerts its functions and discuss recent advances that underscore the multifaceted role of m A in the regulation of gene expression. We highlight advances in our understanding of the regulation of m A deposition on mRNA and its context-dependent effects on mRNA decay and translation, the role of m A methylation of non-coding chromosomal-associated RNA species in regulating transcription, and the activities of the RNA demethylase FTO on diverse substrates. We also discuss emerging evidence for the therapeutic potential of targeting m A regulators in disease.
Topics: Adenosine; Animals; Humans; Methyltransferases; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 33470439
DOI: 10.15252/embj.2020105977 -
Molecular Plant Jan 2020Advances in the detection and mapping of messenger RNA (mRNA) N-methyladenosine (mA) and 5-methylcytosine (mC), and DNA N-methyldeoxyadenosine (6mA) redefined our... (Review)
Review
Advances in the detection and mapping of messenger RNA (mRNA) N-methyladenosine (mA) and 5-methylcytosine (mC), and DNA N-methyldeoxyadenosine (6mA) redefined our understanding of these modifications as additional tiers of epigenetic regulation. In plants, the most prevalent internal mRNA modifications, mA and mC, play crucial and dynamic roles in many processes, including embryo development, stem cell fate determination, trichome branching, leaf morphogenesis, floral transition, stress responses, fruit ripening, and root development. The newly identified and widespread epigenetic marker 6mA DNA methylation is associated with gene expression, plant development, and stress responses. Here, we review the latest research progress on mRNA and DNA epigenetic modifications, including the detection, dynamics, distribution, functions, regulatory proteins, and evolution, with a focus on mA, mC, and 6mA. We also provide some perspectives on future research of the newly identified and unknown epigenetic modifications of mRNA and DNA in plants.
Topics: 5-Methylcytosine; Adenosine; DNA Methylation; Epigenesis, Genetic; Plants; RNA, Messenger
PubMed: 31863849
DOI: 10.1016/j.molp.2019.12.007 -
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