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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 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 -
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 -
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 -
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 May 2019N-methyladenosine (mA) is identified as the most common, abundant and conserved internal transcriptional modification, especially within eukaryotic messenger RNAs... (Review)
Review
N-methyladenosine (mA) is identified as the most common, abundant and conserved internal transcriptional modification, especially within eukaryotic messenger RNAs (mRNAs). MA modification is installed by the mA methyltransferases (METTL3/14, WTAP, RBM15/15B and KIAA1429, termed as "writers"), reverted by the demethylases (FTO and ALKBH5, termed as "erasers") and recognized by mA binding proteins (YTHDF1/2/3, IGF2BP1 and HNRNPA2B1, termed as "readers"). Acumulating evidence shows that, mA RNA methylation has an outsize effect on RNA production/metabolism and participates in the pathogenesis of multiple diseases including cancers. Until now, the molecular mechanisms underlying mA RNA methylation in various tumors have not been comprehensively clarified. In this review, we mainly summarize the recent advances in biological function of mA modifications in human cancer and discuss the potential therapeutic strategies.
Topics: Adenosine; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Neoplasms; Prognosis; RNA Splicing; RNA Stability; RNA, Messenger
PubMed: 31142332
DOI: 10.1186/s12943-019-1033-z -
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