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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 -
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 -
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 -
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 -
Molecular Cell Jul 2016N(6)-methyladenosine (m(6)A) is a prevalent, reversible chemical modification of functional RNAs and is important for central events in biology. The core m(6)A writers...
N(6)-methyladenosine (m(6)A) is a prevalent, reversible chemical modification of functional RNAs and is important for central events in biology. The core m(6)A writers are Mettl3 and Mettl14, which both contain methyltransferase domains. How Mettl3 and Mettl14 cooperate to catalyze methylation of adenosines has remained elusive. We present crystal structures of the complex of Mettl3/Mettl14 methyltransferase domains in apo form as well as with bound S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) in the catalytic site. We determine that the heterodimeric complex of methyltransferase domains, combined with CCCH motifs, constitutes the minimally required regions for creating m(6)A modifications in vitro. We also show that Mettl3 is the catalytically active subunit, while Mettl14 plays a structural role critical for substrate recognition. Our model provides a molecular explanation for why certain mutations of Mettl3 and Mettl14 lead to impaired function of the methyltransferase complex.
Topics: Adenosine; Allosteric Regulation; Binding Sites; Catalytic Domain; HEK293 Cells; Humans; Methylation; Methyltransferases; Models, Molecular; Mutation; Protein Binding; Protein Conformation; RNA; S-Adenosylhomocysteine; S-Adenosylmethionine; Structure-Activity Relationship
PubMed: 27373337
DOI: 10.1016/j.molcel.2016.05.041 -
Immunity, Inflammation and Disease Apr 2023Adenosine receptors are P1 class of purinergic receptors that belong to G protein-coupled receptors. There are 4 subtypes of adenosine receptors, namely A1, A2A, A2B,... (Review)
Review
Adenosine receptors are P1 class of purinergic receptors that belong to G protein-coupled receptors. There are 4 subtypes of adenosine receptors, namely A1, A2A, A2B, and A3. A2AR has a high affinity for the ligand adenosine. Under pathological conditions or external stimuli, ATP is sequentially hydrolyzed to adenosine by CD39 and CD73. The combination of adenosine and A2AR can increase the concentration of cAMP and activate a series of downstream signaling pathways, and further playing the role of immunosuppression and promotion of tumor invasion. A2AR is expressed to some extent on various immune cells, where it is abnormally expressed on immune cells in cancers and autoimmune diseases. A2AR expression also correlates with disease progression. Inhibitors and agonists of A2AR may be potential new strategies for treatment of cancers and autoimmune diseases. We herein briefly reviewed the expression and distribution of A2AR, adenosine/A2AR signaling pathway, expression, and potential as a therapeutic target.
Topics: Humans; Receptor, Adenosine A2A; Adenosine; Autoimmune Diseases; Signal Transduction; Neoplasms
PubMed: 37102661
DOI: 10.1002/iid3.826 -
Current Opinion in Neurobiology Jun 2017Slow wave activity (SWA) during slow wave sleep (SWS) is the best indicator of the sleep homeostasis. The intensity of the SWA observed during SWS that follows prolonged... (Review)
Review
Slow wave activity (SWA) during slow wave sleep (SWS) is the best indicator of the sleep homeostasis. The intensity of the SWA observed during SWS that follows prolonged waking is directly correlated with the duration of prior waking and its intensity decays during SWS suggesting a buildup and a resolution of sleep need. This sleep-homeostasis related SWA results from a buildup and decay of extracellular adenosine that acts at neuronal adenosine A1 receptors to facilitate SWA and is metabolized by adenosine kinase found in glia. This local neuronal-glial circuit for homeostatic SWA is primarily under the requisite control of two genes, the Adora1 and Adk, encoding the responsible adenosine receptor and adenosine's highest affinity metabolizing enzyme.
Topics: Adenosine; Homeostasis; Humans; Neuroglia; Neurons; Sleep
PubMed: 28633050
DOI: 10.1016/j.conb.2017.05.015 -
Neuropharmacology May 2013In rodents, insufficient adenosine produces behavioral and physiological symptoms consistent with several comorbidities of autism. In rodents and humans, stimuli... (Review)
Review
In rodents, insufficient adenosine produces behavioral and physiological symptoms consistent with several comorbidities of autism. In rodents and humans, stimuli postulated to increase adenosine can ameliorate these comorbidities. Because adenosine is a broad homeostatic regulator of cell function and nervous system activity, increasing adenosine's influence might be a new therapeutic target for autism with multiple beneficial effects. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.
Topics: Adenosine; Animals; Autistic Disorder; Humans
PubMed: 22940000
DOI: 10.1016/j.neuropharm.2012.08.013