-
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 -
Cancer Research Jul 2021RNA -methyladenosine (mA) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA mA is regulated by the RNA mA methyltransferases... (Review)
Review
RNA -methyladenosine (mA) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA mA is regulated by the RNA mA methyltransferases methyltransferase-like 3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1-2, YTHDF1-3, IGF2BP1-3, and SND1 (readers). These RNA mA modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA mA modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA mA modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA mA modification protein expression or RNA mA modification protein-induced resistance to cancer therapy.
Topics: Adenosine; Animals; Demethylation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Methylation; Neoplasms; RNA
PubMed: 34228629
DOI: 10.1158/0008-5472.CAN-20-4107 -
Journal of Cellular Physiology Jul 2022This review aims to provide insight into the role of N6-methyladenosine (m6A) modification in neoplastic immunity and subsequent tumorigenesis. m6A modification, which... (Review)
Review
This review aims to provide insight into the role of N6-methyladenosine (m6A) modification in neoplastic immunity and subsequent tumorigenesis. m6A modification, which is catalyzed by methyltransferases, demethylases and reader proteins, has emerged as a widespread regulatory mechanism that controls immune-related gene expression and immune reactions during tumorigenesis. Aberrant m6A modification changes the neoplastic immune response in multiple cancers by regulating immune cell infiltration, tumor-promoting inflammation, immunosuppression, immune surveillance, and antitumor immune responses. m6A modification affects immune cell recruitment and cancer-promoting inflammation in hepatocellular carcinoma (HCC) to alter the progression of HCC. m6A modification has been implicated in the infiltration of immune cells and the activation of immune pathways, changing the proliferation and metastasis of gastric cancer. Immune surveillance and the antitumor immune response in breast cancer were enhanced via m6A modification, which inhibited tumor proliferation. m6A modification participates in neoplastic immunoregulation to influence tumor progression.
Topics: Adenosine; Animals; Carcinogenesis; Cell Transformation, Neoplastic; Humans; Immunity; Inflammation; Neoplasms; Tumor Microenvironment
PubMed: 35342948
DOI: 10.1002/jcp.30730 -
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 -
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 -
Trends in Endocrinology and Metabolism:... Dec 2023Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, influencing numerous regulatory axes and extrahepatic vital organs. The... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, influencing numerous regulatory axes and extrahepatic vital organs. The molecular mechanisms that lead to the progression of NAFLD remain unclear and knowledge on the pathways causing hepatocellular damage followed by lipid accumulation is limited. Recently, a number of studies have shown that mRNA N-methyladenosine (m6A) modification contributes to the progression of NAFLD. In this review, we summarize current knowledge on m6A modification in the metabolic processes associated with NAFLD and discuss the challenges of and prospects for therapeutic avenues based on m6A regulation for the treatment of liver disease.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Adenosine; RNA; Liver
PubMed: 37758602
DOI: 10.1016/j.tem.2023.09.002 -
Expert Review of Molecular Diagnostics Mar 2022N6-Methyladenosine (m6A), the most common and reversible mRNA modification, has attracted considerable attention recently, and accumulating evidence indicates it has an... (Review)
Review
INTRODUCTION
N6-Methyladenosine (m6A), the most common and reversible mRNA modification, has attracted considerable attention recently, and accumulating evidence indicates it has an important role in the progression of ischemic stroke (IS).
AREAS COVERED
We first reviewed m6A methylation modification enzymes, including m6A methyltransferases (METTL3, METTL14, and WTAP), demethylases (FTO and ALKBH5), m6A-binding proteins (YTH domain containing 1/2 [YTHDC1/2], YTHDF1/2/3, and insulin like growth factor 2 mRNA binding protein 1/2/3 [IGF2BP1/2/3]), and their-related functions. An alteration in the m6A methylation profile of IS has been reported and m6A is differentially expressed in IS. Thus, we then focused on the underlying mechanism of m6A methylation in IS and the involvement of atherosclerosis (AS), cerebral ischemia/reperfusion (IR) injury, inflammation, oxidative stress, and apoptosis. Furthermore, we also elucidated the effect of m6A-associated single-nucleotide polymorphisms (SNPs) on stroke and uncovered new causal variants for IS. The clinical application of m6A targeting drugs is still in its infancy and will be available in the future.
EXPERT OPINION
Collectively, the information in the present review is a summary of the latest developments in m6A modification and highlights the mechanisms underlying IS pathogenesis, which may provide novel insights into the mechanisms and therapeutic targets for IS.
Topics: Adenosine; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Humans; Ischemic Stroke; Methylation; Methyltransferases; RNA, Messenger
PubMed: 35236212
DOI: 10.1080/14737159.2022.2049246 -
Neurochemical Research Jan 2023Adenosine, a purine nucleoside with neuromodulatory actions, is part of the purinergic signaling system (PSS). Caenorhabditis elegans is a free-living nematode found in...
Adenosine, a purine nucleoside with neuromodulatory actions, is part of the purinergic signaling system (PSS). Caenorhabditis elegans is a free-living nematode found in soil, used in biological research for its advantages as an alternative experimental model. Since there is a lack of evidence of adenosine's direct actions and the PSS's participation in this animal, such an investigation is necessary. In this research, we aimed to test the effects of acute and chronic adenosine at 1, 5, and 10 mM on nematode's behaviors, morphology, survival after stress conditions, and on pathways related to the response to oxidative stress (DAF-16/FOXO and SKN-1) and genes products downstream these pathways (SOD-3, HSP-16.2, and GCS-1). Acute or chronic adenosine did not alter the worms' morphology analyzed by the worms' length, width, and area, nor interfered with reproductive behavior. On the other hand, acute and chronic adenosine modulated the defecation rate, pharyngeal pumping rate, and locomotion, in addition, to interacting with stress response pathways in C. elegans. Adenosine interfered in the speed and mobility of the worms analyzed. In addition, both acute and chronic adenosine presented modulatory effects on oxidative stress response signaling. Acute adenosine prevented the heat-induced-increase of DAF-16 activation and SOD-3 levels, while chronic adenosine per se induced DAF-16 activation and prevented heat-induced-increase of HSP-16.2 and SKN-1 levels. Together, these results indicate that exogenous adenosine has physiological and biochemical effects on C. elegans and describes possible purinergic signaling in worms.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Adenosine; Oxidative Stress; Superoxide Dismutase; Longevity; Forkhead Transcription Factors
PubMed: 36018438
DOI: 10.1007/s11064-022-03727-5 -
The Laryngoscope Sep 2023Viral acute rhinosinusitis (ARS) is the leading cause of work and school absence and antibiotic over-prescription. There are limited treatment options available to...
OBJECTIVE
Viral acute rhinosinusitis (ARS) is the leading cause of work and school absence and antibiotic over-prescription. There are limited treatment options available to ameliorate the symptoms caused by viral ARS. We have previously demonstrated that topical adenosine treatment enhances mucociliary clearance in the sino-nasal tract. Here, we assessed the therapeutic potential of topical adenosine in a mouse model of viral ARS.
METHODS
The effect of topical adenosine on inflammatory response and mucin gene expression was examined in a mouse model of viral ARS induced by respiratory syncytial virus (RSV) nasal-only infection. We also investigated the inflammatory effect of both endogenous and exogenous adenosine in the sino-nasal tract.
RESULTS
Topical adenosine significantly inhibited the expression of pro-inflammatory cytokines, goblet hyperplasia, mucin expression, and cell damage in the nose of mice with viral ARS. This treatment did not prolong virus clearance. This inhibitory effect was primarily mediated by the A adenosine receptor (AR). Although previous studies have shown that adenosine induces a robust inflammatory response in the lungs, neither endogenous nor exogenous adenosine produced inflammation in the sino-nasal tract. Instead, exogenous adenosine inhibited the baseline expression of TNF and IL-1β in the nose. Additionally, baseline expression of ARs was lower in the nose than that in the trachea and lungs.
CONCLUSION
We demonstrated that intranasal adenosine administration effectively decreased inflammation and mucus production in a mouse model of viral ARS.
LEVEL OF EVIDENCE
N/A Laryngoscope, 133:2095-2103, 2023.
Topics: Mice; Animals; Adenosine; Inflammation; Sinusitis; Mucins; Disease Models, Animal; Mucus
PubMed: 36576070
DOI: 10.1002/lary.30541 -
Molecular Therapy : the Journal of the... May 2021The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched... (Review)
Review
The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched topic. The TME can be described in terms of hypoxia, metabolic dysregulation, immune escape, and chronic inflammation. RNA methylation, an epigenetic modification, has recently been found to have a pivotal role in shaping the TME. The N-methylation of adenosine (mA) modification is the most common type of RNA methylation that occurs in the N-position of adenosine, which is the primary internal modification of eukaryotic mRNA. Compelling evidence has demonstrated that mA regulates transcriptional and protein expression through splicing, translation, degradation, and export, thereby mediating the biological processes of cancer cells and/or stromal cells and characterizing the TME. The TME also has a crucial role in the complicated regulatory network of mA modifications and, subsequently, influences tumor initiation, progression, and therapy responses. In this review, we describe the features of the TME and how the mA modification modulates and interacts with it. We also focus on various factors and pathways involved in mA methylation. Finally, we discuss potential therapeutic strategies and prognostic biomarkers with respect to the TME and mA modification.
Topics: Adenosine; Biomarkers, Tumor; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Tumor Microenvironment
PubMed: 33839323
DOI: 10.1016/j.ymthe.2021.04.009