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International Journal of Biological... 2020N6-methyladenosine (mA) is identified as the most prevalent and abundant internal RNA modification, especially within eukaryotic mRNAs, which has attracted much... (Review)
Review
N6-methyladenosine (mA) is identified as the most prevalent and abundant internal RNA modification, especially within eukaryotic mRNAs, which has attracted much attention in recent years since its importance for regulating gene expression and deciding cell fate. mA modification is installed by RNA methyltransferases METTL3, METTL14 and WTAP (Writers), removed by the demethylases FTO and ALKBH5 (Erasers) and recognized by mA binding proteins, such as YT521-B homology YTH domain-containing proteins (Readers). Accumulating evidence shows that mA RNA methylation participates in almost all aspects of RNA processing, implying an association with important bioprocesses. In this review, we mainly summarize and discuss the functional relevance and importance of mA modification in cellular processes.
Topics: Adenosine; Animals; Gene Expression Regulation; Humans; Protein Biosynthesis; RNA; RNA Splicing; RNA, Messenger
PubMed: 32398960
DOI: 10.7150/ijbs.45231 -
RNA (New York, N.Y.) Feb 2016Over 100 distinct chemical modifications can be catalyzed on RNA post-synthesis, potentially serving as a post-transcriptional regulatory layer of gene expression. This... (Review)
Review
Over 100 distinct chemical modifications can be catalyzed on RNA post-synthesis, potentially serving as a post-transcriptional regulatory layer of gene expression. This review focuses on recent advances, knowledge gaps, and challenges pertaining to N6-methyladenosine (m6A), an abundant modification of mRNA for which substantial progress has been made in recent years. The discussed aspects are also very relevant for a wide range of additional modifications on mRNA collectively coined the epitranscriptome.
Topics: Adenosine; Animals; Epigenesis, Genetic; Humans; Methylation; Mice; RNA Processing, Post-Transcriptional; RNA, Messenger; Transcriptome
PubMed: 26787305
DOI: 10.1261/rna.054502.115 -
Annual Review of Biochemistry Jun 2023Over the past decade, mRNA modifications have emerged as important regulators of gene expression control in cells. Fueled in large part by the development of tools for... (Review)
Review
Over the past decade, mRNA modifications have emerged as important regulators of gene expression control in cells. Fueled in large part by the development of tools for detecting RNA modifications transcriptome wide, researchers have uncovered a diverse epitranscriptome that serves as an additional layer of gene regulation beyond simple RNA sequence. Here, we review the proteins that write, read, and erase these marks, with a particular focus on the most abundant internal modification, -methyladenosine (mA). We first describe the discovery of the key enzymes that deposit and remove mA and other modifications and discuss how our understanding of these proteins has shaped our views of modification dynamics. We then review current models for the function of mA reader proteins and how our knowledge of these proteins has evolved. Finally, we highlight important future directions for the field and discuss key questions that remain unanswered.
Topics: RNA, Messenger; Adenosine; Gene Expression Regulation; Proteins; Transcriptome
PubMed: 37068770
DOI: 10.1146/annurev-biochem-052521-035330 -
Annals of Hepatology 2021N6-methyladenosine (mA) is the most thoroughly studied type of internal RNA modification, as this epigenetic modification is the most abundant in eukaryotic RNAs to... (Review)
Review
N6-methyladenosine (mA) is the most thoroughly studied type of internal RNA modification, as this epigenetic modification is the most abundant in eukaryotic RNAs to date. This modification occurs in various types of RNAs and plays significant roles in dominant RNA-related processes, such as translation, splicing, export and degradation. These processes are catalyzed by three types of prominent enzymes: writers, erasers and readers. Increasing evidence has shown that mA modification is vital for the regulation of gene expression, carcinogenesis, tumor progression and other abnormal changes, and recent studies have shown that mA is important in the development of hepatocellular carcinoma (HCC). Herein, we summarize the nature and regulatory mechanisms of mA modification, including its role in the pathogenesis of HCC and related chronic liver diseases. We also highlight the clinical significance and future strategies involving RNA mA modifications in HCC.
Topics: Adenosine; Carcinoma, Hepatocellular; Humans; Liver Neoplasms
PubMed: 34555511
DOI: 10.1016/j.aohep.2021.100538 -
Biopolymers Jan 2021Chemical modifications on RNA can regulate fundamental biological processes. Recent efforts have illuminated the chemical diversity of posttranscriptional... (Review)
Review
Chemical modifications on RNA can regulate fundamental biological processes. Recent efforts have illuminated the chemical diversity of posttranscriptional ("epitranscriptomic") modifications on eukaryotic messenger RNA and have begun to elucidate their biological roles. In this review, we discuss our current molecular understanding of epitranscriptomic RNA modifications and their effects on gene expression. In particular, we highlight the role of modifications in mediating RNA-protein interactions, RNA structure, and RNA-RNA base pairing, and how these macromolecular interactions control biological processes in the cell.
Topics: Adenosine; Base Pairing; Cytidine; Gene Expression Regulation; RNA; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 33001446
DOI: 10.1002/bip.23403 -
Current Heart Failure Reports Oct 2020Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA... (Review)
Review
PURPOSE OF REVIEW
Post-transcriptional modifications are key regulators of gene expression that allow the cell to respond to environmental stimuli. The most abundant internal mRNA modification is N6-methyladenosine (mA), which has been shown to be involved in the regulation of RNA splicing, localization, translation, and decay. It has also been implicated in a wide range of diseases, and here, we review recent evidence of mA's involvement in cardiac pathologies and processes.
RECENT FINDINGS
Studies have primarily relied on gain and loss of function models for the enzymes responsible for adding and removing the mA modification. Results have revealed a multifaceted role for mA in the heart's response to myocardial infarction, pressure overload, and ischemia/reperfusion injuries. Genome-wide analyses of mRNAs that are differentially methylated during cardiac stress have highlighted the importance of mA in regulating the translation of specific categories of transcripts implicated in pathways such as calcium handling, cell growth, autophagy, and adrenergic signaling in cardiomyocytes. Regulation of gene expression by mA is critical for cardiomyocyte homeostasis and stress responses, suggesting a key role for this modification in cardiac pathophysiology.
Topics: Adenosine; Epigenesis, Genetic; Genome-Wide Association Study; Heart Failure; Humans; RNA, Messenger; Signal Transduction
PubMed: 32813261
DOI: 10.1007/s11897-020-00473-z -
Journal For Immunotherapy of Cancer Feb 2022Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and... (Review)
Review
Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and CD39 in development. Through a cyclic-AMP-mediated intracellular cascade, adenosine shifts the cytokine and cellular profile of the tumor microenvironment away from cytotoxic T cell inflammation toward one of immune tolerance. A perpetuating cycle of tumor cell proliferation, tissue injury, dysregulated angiogenesis, and hypoxia promote adenosine accumulation via ATP catabolism. Adenosine receptor (eg, A2AR, A2BR) stimulation of both the innate and adaptive cellular precursors lead to immunosuppressive phenotypic differentiation. Preclinical work in various tumor models with adenosine receptor inhibition has demonstrated restoration of immune cell function and tumor regression. Given the broad activity but known limitations of anti-programmed cell death protein (PD1) therapy and other checkpoint inhibitors, ongoing studies have sought to augment the successful outcomes of anti-PD1 therapy with combinatorial approaches, particularly adenosine signaling blockade. Preliminary data have demonstrated an optimal safety profile and enhanced overall response rates in several early phase clinical trials with A2AR and more recently CD73 inhibitors. However, beneficial outcomes for both monotherapy and combinations have been mostly lower than expected based on preclinical studies, indicating a need for more nuanced patient selection or biomarker integration that might predict and optimize patient outcomes. In the context of known immuno-oncology biomarkers such as tumor mutational burden and interferon-associated gene expression, a comparison of adenosine-related gene signatures associated with clinical response indicates an underlying biology related to immunosuppression, angiogenesis, and T cell inflammation. Importantly, though, adenosine associated gene expression may point to a unique intratumoral phenotype independent from IFN-γ related pathways. Here, we discuss the cellular and molecular mechanisms of adenosine-mediated immunosuppression, preclinical investigation of adenosine signaling blockade, recent response data from clinical trials with A2AR, CD73, CD39 and PD1/L1 inhibitors, and ongoing development of predictive gene signatures to enhance combinatorial immune-based therapies.
Topics: Adenosine; Humans; Immunotherapy; Neoplasms
PubMed: 35135866
DOI: 10.1136/jitc-2021-004089 -
Pharmacology Research & Perspectives Aug 2019Adenosine (ADO) is an endogenous protective regulator that restores cellular energy balance in response to tissue trauma. Extracellular ADO has a half-life of the order... (Review)
Review
Adenosine (ADO) is an endogenous protective regulator that restores cellular energy balance in response to tissue trauma. Extracellular ADO has a half-life of the order of seconds thus restricting its actions to tissues and cellular sites where it is released. Adenosine kinase (AK, ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) is a cytosolic enzyme that is the rate-limiting enzyme controlling extracellular ADO concentrations. Inhibition of AK can effectively increase ADO extracellular concentrations at tissue sites where pathophysiological changes occur. Highly potent and selective nucleoside and non-nucleoside AK inhibitors were discovered in the late 1990s that showed in vivo effects consistent with the augmentation of the actions of endogenous ADO in experimental models of pain, inflammation, and seizure activity. These data supported clinical development of several AK inhibitors for the management of epilepsy and chronic pain. However, early toxicological data demonstrated that nucleoside and non-nucleoside chemotypes produced hemorrhagic microfoci in brain in an apparent ADO receptor-dependent fashion. An initial oral report of these important toxicological findings was presented at an international conference but a detailed description of these data has not appeared in the peer-reviewed literature. In the two decades following the demise of these early AK-based clinical candidates, interest in AK inhibition has renewed based on preclinical data in the areas of renal protection, diabetic retinopathy, cardioprotection, and neurology. This review provides a summary of the pharmacology and toxicology data for several AK inhibitor chemotypes and the resulting translational issues associated with the development of AK inhibitors as viable therapeutic interventions.
Topics: Adenosine; Adenosine Kinase; Animals; Drug Development; Enzyme Inhibitors; Humans; Molecular Structure
PubMed: 31367385
DOI: 10.1002/prp2.506 -
Trends in Cell Biology Feb 2018N-Methyladenosine (mA) is the most prevalent post-transcriptional modification of eukaryotic mRNA and long noncoding RNA. mA mediates its effects primarily by recruiting... (Review)
Review
N-Methyladenosine (mA) is the most prevalent post-transcriptional modification of eukaryotic mRNA and long noncoding RNA. mA mediates its effects primarily by recruiting proteins, including the multiprotein eukaryotic initiation factor 3 complex and a set of proteins that contain the YTH domain. Here we describe the mechanisms by which YTH domain-containing proteins bind mA and influence the fate of mA-containing RNA in mammalian cells. We discuss the diverse, and occasionally contradictory, functions ascribed to these proteins and the emerging concepts that are influencing our understanding of these proteins and their effects on the epitranscriptome.
Topics: Adenosine; Amino Acid Sequence; Animals; Carrier Proteins; Humans; Phylogeny; RNA, Long Noncoding; RNA, Messenger; Reading Frames; Transcriptome
PubMed: 29103884
DOI: 10.1016/j.tcb.2017.10.001 -
Science (New York, N.Y.) Jun 2016RNA contains more than 100 distinct modifications that promote the functions of stable noncoding RNAs in translation and splicing. Recent technical advances have... (Review)
Review
RNA contains more than 100 distinct modifications that promote the functions of stable noncoding RNAs in translation and splicing. Recent technical advances have revealed widespread and sparse modification of messenger RNAs with N(6)-methyladenosine (m(6)A), 5-methylcytosine (m(5)C), and pseudouridine (Ψ). Here we discuss the rapidly evolving understanding of the location, regulation, and function of these dynamic mRNA marks, collectively termed the epitranscriptome. We highlight differences among modifications and between species that could instruct ongoing efforts to understand how specific mRNA target sites are selected and how their modification is regulated. Diverse molecular consequences of individual m(6)A modifications are beginning to be revealed, but the effects of m(5)C and Ψ remain largely unknown. Future work linking molecular effects to organismal phenotypes will broaden our understanding of mRNA modifications as cell and developmental regulators.
Topics: 5-Methylcytosine; Adenosine; Animals; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Humans; Methylation; Methyltransferases; Pseudouridine; RNA Processing, Post-Transcriptional; RNA, Messenger; Transcriptome
PubMed: 27313037
DOI: 10.1126/science.aad8711