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RNA Biology Mar 2017Cellular RNAs with diverse chemical modifications have been observed, and N-methyladenosine (mA) is one of the most abundant internal modifications found on mRNA and... (Review)
Review
Cellular RNAs with diverse chemical modifications have been observed, and N-methyladenosine (mA) is one of the most abundant internal modifications found on mRNA and non-coding RNAs, playing a vital role in diverse biologic processes. In humans, mA modification is catalyzed by the METTL3-METTL14 methyltransferase complex, which is regulated by WTAP and another factor. Three groups have recently and independently reported the structure of this complex with or without cofactors. Here, we focus on the detailed mechanism of the mA methyltransferase complex and the properties of each subunit. METTL3 is predominantly catalytic, with a function reminiscent of N-adenine DNA methyltransferase systems, whereas METTL14 appears to be a pseudomethyltransferase that stabilizes METTL3 and contributes to target RNA recognition. The structural and biochemical characterization of the METTL3-METTL14 complex is a major step toward understanding the function of mA modification and developing mA-related therapies.
Topics: Adenosine; Catalysis; Cell Cycle Proteins; Epigenesis, Genetic; Humans; Methylation; Methyltransferases; Nuclear Proteins; RNA; RNA Splicing Factors; Structure-Activity Relationship
PubMed: 28121234
DOI: 10.1080/15476286.2017.1282025 -
Genome Biology Oct 2017RNA contains over 150 types of chemical modifications. Although many of these chemical modifications were discovered several decades ago, their functions were not... (Review)
Review
RNA contains over 150 types of chemical modifications. Although many of these chemical modifications were discovered several decades ago, their functions were not immediately apparent. Discoveries of RNA demethylases, along with advances in mass spectrometry and high-throughput sequencing techniques, have caused research into RNA modifications to progress at an accelerated rate. Post-transcriptional RNA modifications make up an epitranscriptome that extensively regulates gene expression and biological processes. Here, we present an overview of recent advances in the field that are shaping our understanding of chemical modifications, their impact on development and disease, and the dynamic mechanisms through which they regulate gene expression.
Topics: Adenosine; Animals; Cell Differentiation; Growth and Development; Humans; Neoplasms; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Transfer; Transcriptome
PubMed: 29061143
DOI: 10.1186/s13059-017-1336-6 -
Molecular Cell Jan 2018N-methyladenosine (mA) and adenosine-to-inosine (A-to-I) editing are two of the most abundant RNA modifications, both at adenosines. Yet, the interaction of these two...
N-methyladenosine (mA) and adenosine-to-inosine (A-to-I) editing are two of the most abundant RNA modifications, both at adenosines. Yet, the interaction of these two types of adenosine modifications is largely unknown. Here we show a global A-to-I difference between mA-positive and mA-negative RNA populations. Both the presence and extent of A-to-I sites in mA-negative RNA transcripts suggest a negative correlation between mA and A-to-I. Suppression of mA-catalyzing enzymes results in global A-to-I RNA editing changes. Further depletion of mA modification increases the association of mA-depleted transcripts with adenosine deaminase acting on RNA (ADAR) enzymes, resulting in upregulated A-to-I editing on the same mA-depleted transcripts. Collectively, the effect of mA on A-to-I suggests a previously underappreciated interplay between two distinct and abundant RNA modifications, highlighting a complex epitranscriptomic landscape.
Topics: Adenosine; Adenosine Deaminase; Cell Line, Tumor; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humans; Inosine; Methyltransferases; RNA; RNA Editing; RNA-Binding Proteins
PubMed: 29304330
DOI: 10.1016/j.molcel.2017.12.006 -
Neuropharmacology Sep 2023About 50 years elapsed from the publication of the first full paper on the neuromodulatory action of adenosine at a 'simple' synapse model, the neuromuscular junction... (Review)
Review
About 50 years elapsed from the publication of the first full paper on the neuromodulatory action of adenosine at a 'simple' synapse model, the neuromuscular junction (Ginsborg and Hirst, 1972). In that study adenosine was used as a tool to increase cyclic AMP and for the great surprise, it decreased rather than increased neurotransmitter release, and for a further surprise, its action was prevented by theophylline, at the time only known as inhibitor of phosphodiesterases. These intriguing observations opened the curiosity for immediate studies relating the action of adenine nucleotides, known to be released together with neurotransmitters, to that of adenosine (Ribeiro and Walker, 1973, 1975). Our understanding on the ways adenosine uses to modulate synapses, circuits, and brain activity, vastly expanded since then. However, except for A receptors, whose actions upon GABAergic neurons of the striatum are well known, most of the attention given to the neuromodulatory action of adenosine has been focusing upon excitatory synapses. Evidence is growing that GABAergic transmission is also a target for adenosinergic neuromodulation through A and A receptors. Some o these actions have specific time windows during brain development, and others are selective for specific GABAergic neurons. Both tonic and phasic GABAergic transmission can be affected, and either neurons or astrocytes can be targeted. In some cases, those effects result from a concerted action with other neuromodulators. Implications of these actions in the control of neuronal function/dysfunction will be the focus of this review. This article is part of the Special Issue on "Purinergic Signaling: 50 years".
Topics: Synaptic Transmission; Synapses; Adenosine; Neuromuscular Junction; GABAergic Neurons
PubMed: 37225084
DOI: 10.1016/j.neuropharm.2023.109600 -
PLoS Pathogens Mar 2017
Review
Topics: Adenosine; Animals; Humans; RNA Processing, Post-Transcriptional; RNA, Viral; Virus Diseases
PubMed: 28278189
DOI: 10.1371/journal.ppat.1006188 -
Cell Death & Disease Oct 2021Proper follicle development is very important for the production of mature oocytes, which is essential for the maintenance of female fertility. This complex biological...
Proper follicle development is very important for the production of mature oocytes, which is essential for the maintenance of female fertility. This complex biological process requires precise gene regulation. The most abundant modification of mRNA, N-methyladenosine (mA), is involved in many RNA metabolism processes, including RNA splicing, translation, stability, and degradation. Here, we report that mA plays essential roles during oocyte and follicle development. Oocyte-specific inactivation of the key mA methyltransferase Mettl3 with Gdf9-Cre caused DNA damage accumulation in oocytes, defective follicle development, and abnormal ovulation. Mechanistically, combined RNA-seq and mA methylated RNA immunoprecipitation sequencing (MeRIP-seq) data from oocytes revealed, that we found METTL3 targets Itsn2 for mA modification and then enhances its stability to influence the oocytes meiosis. Taken together, our findings highlight the crucial roles of mRNA mA modification in follicle development and coordination of RNA stabilization during oocyte growth.
Topics: Adenosine; Animals; Female; Methyltransferases; Mice; Oocytes; Ovarian Follicle
PubMed: 34689175
DOI: 10.1038/s41419-021-04272-9 -
International Journal of Molecular... Jun 2019Among a number of mRNA modifications, N6‑methyladenosine (m6A) modification is the most common type in eukaryotes and nuclear‑replicating viruses. m6A has a... (Review)
Review
Among a number of mRNA modifications, N6‑methyladenosine (m6A) modification is the most common type in eukaryotes and nuclear‑replicating viruses. m6A has a significant role in numerous cancer types, including leukemia, brain tumors, liver cancer, breast cancer and lung cancer. Although m6A methyltransferases are essential during RNA modifications, the biological functions of m6A and the underlying mechanisms remain to be fully elucidated, predominantly due to the limited detection methods for m6A. In the present review, the currently available m6A detection methods and the respective scope of their applications are presented to facilitate the further investigation of the roles of m6A in biological process.
Topics: Adenosine; Animals; Biosensing Techniques; Blotting, Northern; Chromatography, High Pressure Liquid; Electrochemical Techniques; Humans; Immunoblotting; Immunoprecipitation; Methylation; Neoplasms; RNA; Sequence Analysis, RNA
PubMed: 31017262
DOI: 10.3892/ijmm.2019.4169 -
Open Biology Sep 2020RNA mA methylation is a post-transcriptional modification that occurs at the nitrogen-6 position of adenine. This dynamically reversible modification is installed,... (Review)
Review
RNA mA methylation is a post-transcriptional modification that occurs at the nitrogen-6 position of adenine. This dynamically reversible modification is installed, removed and recognized by methyltransferases, demethylases and readers, respectively. This modification has been found in most eukaryotic mRNA, tRNA, rRNA and other non-coding RNA. Recent studies have revealed important regulatory functions of the mA including effects on gene expression regulation, organism development and cancer development. In this review, we summarize the discovery and features of mA, and briefly introduce the mammalian mA writers, erasers and readers. Finally, we discuss progress in identifying additional functions of mA and the outstanding questions about the regulatory effect of this widespread modification.
Topics: Adenosine; Animals; Disease Susceptibility; Gene Expression Regulation; Humans; Methylation; RNA Processing, Post-Transcriptional; RNA Splicing; RNA Stability; RNA Transport; RNA, Messenger; RNA-Binding Proteins; Transcription, Genetic
PubMed: 32898471
DOI: 10.1098/rsob.200091 -
Molecular Cancer Jun 2020Since the breakthrough discoveries of DNA and histone modifications, the field of RNA modifications has gained increasing interest in the scientific community. The... (Review)
Review
Since the breakthrough discoveries of DNA and histone modifications, the field of RNA modifications has gained increasing interest in the scientific community. The discovery of N6-methyladenosine (m6A), a predominantly internal epigenetic modification in eukaryotes mRNA, heralded the creation of the field of epi-transcriptomics. This post-transcriptional RNA modification is dynamic and reversible, and is regulated by methylases, demethylases and proteins that preferentially recognize m6A modifications. Altered m6A levels affect RNA processing, degradation and translation, thereby disrupting gene expression and key cellular processes, ultimately resulting in tumor initiation and progression. Furthermore, inhibitors and regulators of m6A-related factors have been explored as therapeutic approaches for treating cancer. In the present review, the mechanisms of m6A RNA modification, the clinicopathological relevance of m6A alterations, the type and frequency of alterations and the multiple functions it regulates in different types of cancer are discussed.
Topics: Adenosine; Biomarkers, Tumor; DNA Methylation; Disease Progression; Epigenesis, Genetic; Humans; Methyltransferases; Neoplasms
PubMed: 32513173
DOI: 10.1186/s12943-020-01216-3 -
Biochimica Et Biophysica Acta. Gene... 2021R-loop represents a prevalent and specialized chromatin structure critically involved in a wide range of biological processes. In particular, co-transcriptional R-loops,... (Review)
Review
R-loop represents a prevalent and specialized chromatin structure critically involved in a wide range of biological processes. In particular, co-transcriptional R-loops, produced often due to RNA polymerase pausing or RNA biogenesis malfunction, can initiate molecular events to context-dependently regulate local gene transcription and crosstalk with chromatin modifications. Cellular "readers" of R-loops are identified, exerting crucial impacts on R-loop homeostasis and gene regulation. Mounting evidence also supports R-loop deregulation as a frequent, sometimes initiating, event during the development of human pathologies, notably cancer and neurological disorder. The purpose of this review is to cover recent advances in understanding the fundamentals of R-loop biology, which have started to unveil complex interplays of R-loops with factors involved in various biological processes such as transcription, RNA processing and epitranscriptomic modification (such as N6-methyladenosine), DNA damage sensing and repair, and epigenetic regulation.
Topics: Adenosine; Animals; DNA Damage; DNA Methylation; DNA Repair; Epigenesis, Genetic; Genomic Instability; Humans; R-Loop Structures; RNA Processing, Post-Transcriptional; Transcription, Genetic
PubMed: 34461314
DOI: 10.1016/j.bbagrm.2021.194750