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Molecular Cancer Mar 2023N6-methyladenosine (mA) methylation is the most universal internal modification in eukaryotic mRNA. With elaborate functions executed by mA writers, erasers, and... (Review)
Review
N6-methyladenosine (mA) methylation is the most universal internal modification in eukaryotic mRNA. With elaborate functions executed by mA writers, erasers, and readers, mA modulation is involved in myriad physiological and pathological processes. Extensive studies have demonstrated mA modulation in diverse tumours, with effects on tumorigenesis, metastasis, and resistance. Recent evidence has revealed an emerging role of mA modulation in tumour immunoregulation, and divergent mA methylation patterns have been revealed in the tumour microenvironment. To depict the regulatory role of mA methylation in the tumour immune microenvironment (TIME) and its effect on immune evasion, this review focuses on the TIME, which is characterized by hypoxia, metabolic reprogramming, acidity, and immunosuppression, and outlines the mA-regulated TIME and immune evasion under divergent stimuli. Furthermore, mA modulation patterns in anti-tumour immune cells are summarized.
Topics: Humans; Methylation; Immune Evasion; Tumor Microenvironment; Adenosine; Carcinogenesis
PubMed: 36859310
DOI: 10.1186/s12943-022-01704-8 -
Molecular Cancer Jul 2022The resistance of tumor cells to therapy severely impairs the efficacy of treatment, leading to recurrence and metastasis of various cancers. Clarifying the underlying... (Review)
Review
The resistance of tumor cells to therapy severely impairs the efficacy of treatment, leading to recurrence and metastasis of various cancers. Clarifying the underlying mechanisms of therapeutic resistance may provide new strategies for overcoming cancer resistance. N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotes, and is involved in the regulation of RNA splicing, translation, transport, degradation, stability and processing, thus affecting several physiological processes and cancer progression. As a novel type of multifunctional non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been demonstrated to play vital roles in anticancer therapy. Currently, accumulating studies have revealed the mutual regulation of m6A modification and circRNAs, and their interaction can further influence the sensitivity of cancer treatment. In this review, we mainly summarized the recent advances of m6A modification and circRNAs in the modulation of cancer therapeutic resistance, as well as their interplay and potential mechanisms, providing promising insights and future directions in reversal of therapeutic resistance in cancer.
Topics: Adenosine; Drug Resistance, Neoplasm; Humans; Methylation; Neoplasms; RNA, Circular
PubMed: 35843942
DOI: 10.1186/s12943-022-01620-x -
Frontiers in Immunology 2023Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney diseases, and... (Review)
Review
Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney diseases, and autoimmune diseases have high incidence rates, still threaten human health, and represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis of various diseases. As the most widely discussed m6A methyltransferase, the pathogenic role of METTL3 in inflammatory diseases has become a research hotspot, but there has been no comprehensive review of the topic. Here, we summarize the expression changes, modified target genes, and pathogenesis related to METTL3 in cardiovascular, metabolic, degenerative, immune, and infectious diseases, as well as tumors. In addition to epithelial cells, endothelial cells, and fibroblasts, METTL3 also regulates the function of inflammation-related immune cells, including macrophages, neutrophils, dendritic cells, Th17 cells, and NK cells. Regarding therapeutic applications, METTL3 serves as a target for the treatment of inflammatory diseases with natural plant drug components, such as emodin, cinnamaldehyde, total flavonoids of , and resveratrol. This review focuses on recent advances in the initiation, development, and therapeutic application of METTL3 in inflammatory diseases. Knowledge of the specific regulatory mechanisms involving METTL3 can help to deepen understanding of inflammatory diseases and lay the foundation for the development of precisely targeted drugs to address inflammatory processes.
Topics: Humans; Endothelial Cells; Methyltransferases; Adenosine; Atherosclerosis; Autoimmune Diseases; Cardiovascular Diseases
PubMed: 37671161
DOI: 10.3389/fimmu.2023.1221609 -
Cell Dec 2023Transfer RNA (tRNA) modifications are critical for protein synthesis. Queuosine (Q), a 7-deaza-guanosine derivative, is present in tRNA anticodons. In vertebrate tRNAs...
Transfer RNA (tRNA) modifications are critical for protein synthesis. Queuosine (Q), a 7-deaza-guanosine derivative, is present in tRNA anticodons. In vertebrate tRNAs for Tyr and Asp, Q is further glycosylated with galactose and mannose to generate galQ and manQ, respectively. However, biogenesis and physiological relevance of Q-glycosylation remain poorly understood. Here, we biochemically identified two RNA glycosylases, QTGAL and QTMAN, and successfully reconstituted Q-glycosylation of tRNAs using nucleotide diphosphate sugars. Ribosome profiling of knockout cells revealed that Q-glycosylation slowed down elongation at cognate codons, UAC and GAC (GAU), respectively. We also found that galactosylation of Q suppresses stop codon readthrough. Moreover, protein aggregates increased in cells lacking Q-glycosylation, indicating that Q-glycosylation contributes to proteostasis. Cryo-EM of human ribosome-tRNA complex revealed the molecular basis of codon recognition regulated by Q-glycosylations. Furthermore, zebrafish qtgal and qtman knockout lines displayed shortened body length, implying that Q-glycosylation is required for post-embryonic growth in vertebrates.
Topics: Animals; Humans; Rats; Anticodon; Cell Line; Codon; Glycosylation; Nucleoside Q; RNA, Transfer; Swine; Zebrafish; Nucleic Acid Conformation
PubMed: 37992713
DOI: 10.1016/j.cell.2023.10.026 -
Nature Genetics Aug 2021The most prevalent post-transcriptional mRNA modification, N-methyladenosine (mA), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains...
The most prevalent post-transcriptional mRNA modification, N-methyladenosine (mA), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains uncharted. Here we report 129 transcriptome-wide mA profiles, covering 91 individuals and 4 tissues (brain, lung, muscle and heart) from GTEx/eGTEx. We integrate these with interindividual genetic and expression variation, revealing 8,843 tissue-specific and 469 tissue-shared mA quantitative trait loci (QTLs), which are modestly enriched in, but mostly orthogonal to, expression QTLs. We integrate mA QTLs with disease genetics, identifying 184 GWAS-colocalized mA QTL, including brain mA QTLs underlying neuroticism, depression, schizophrenia and anxiety; lung mA QTLs underlying expiratory flow and asthma; and muscle/heart mA QTLs underlying coronary artery disease. Last, we predict novel mA regulators that show preferential binding in mA QTLs, protein interactions with known mA regulators and expression correlation with the mA levels of their targets. Our results provide important insights and resources for understanding both cis and trans regulation of epitranscriptomic modifications, their interindividual variation and their roles in human disease.
Topics: Adenosine; Brain; Genome-Wide Association Study; Heart; Humans; Lung; Methylation; Muscle, Skeletal; Organ Specificity; Polymorphism, Single Nucleotide; Quantitative Trait Loci; RNA Processing, Post-Transcriptional; RNA-Binding Proteins; Reproducibility of Results
PubMed: 34211177
DOI: 10.1038/s41588-021-00890-3 -
Nature Methods Dec 2019N-methyladenosine (mA) is a widespread RNA modification that influences nearly every aspect of the messenger RNA lifecycle. Our understanding of mA has been facilitated...
N-methyladenosine (mA) is a widespread RNA modification that influences nearly every aspect of the messenger RNA lifecycle. Our understanding of mA has been facilitated by the development of global mA mapping methods, which use antibodies to immunoprecipitate methylated RNA. However, these methods have several limitations, including high input RNA requirements and cross-reactivity to other RNA modifications. Here, we present DART-seq (deamination adjacent to RNA modification targets), an antibody-free method for detecting mA sites. In DART-seq, the cytidine deaminase APOBEC1 is fused to the mA-binding YTH domain. APOBEC1-YTH expression in cells induces C-to-U deamination at sites adjacent to mA residues, which are detected using standard RNA-seq. DART-seq identifies thousands of mA sites in cells from as little as 10 ng of total RNA and can detect mA accumulation in cells over time. Additionally, we use long-read DART-seq to gain insights into mA distribution along the length of individual transcripts.
Topics: APOBEC-1 Deaminase; Adenosine; Base Sequence; Deamination; HEK293 Cells; Humans; Transcriptome
PubMed: 31548708
DOI: 10.1038/s41592-019-0570-0 -
ELife Dec 2023Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Topics: Leishmania donovani; Ligands; Phosphotransferases; Cyclic AMP-Dependent Protein Kinases; Purine Nucleosides; Trypanosoma brucei brucei
PubMed: 38126364
DOI: 10.7554/eLife.94720 -
Science Translational Medicine Jun 2022Tumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can...
Tumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can trigger adenosine triphosphate (ATP) release from tumor cells, causing rapid formation of adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate cancer therapy-induced immunogenic cell death including ATP release and to limit ATP degradation into adenosine, in order to achieve durable antitumor immune response. Our approach was to construct reactive oxygen species (ROS)-producing nanoparticles that carry an ectonucleotidase inhibitor ARL67156 by electronic interaction and phenylboronic ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced ATP release from MOC1 cancer cells in vitro and triggered the cleavage of phenylboronic ester, facilitating the release of ARL67156 from the nanoparticles. ARL67156 prevented conversion of ATP to adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse tumor models. Nanoparticle-based ROS-responsive drug delivery reprogramed the immunogenic landscape in tumors, eliciting tumor-specific T cell responses and tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-programmed cell death protein 1 (PD1) immunotherapy, and the combination resulted in tumor regression in a 4T1 breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human cancers.
Topics: Adenosine; Adenosine Triphosphate; Animals; Cell Line, Tumor; Esters; Humans; Immunosuppression Therapy; Mice; Nanoparticles; Neoplasms; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 35675434
DOI: 10.1126/scitranslmed.abh1261 -
Phytomedicine : International Journal... Dec 2023Current evidence indicates a rising global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD), which is closely associated to conditions such as obesity,...
BACKGROUND
Current evidence indicates a rising global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD), which is closely associated to conditions such as obesity, dyslipidemia, insulin resistance, and metabolic syndrome. The relationship between the gut microbiome and metabolites in NAFLD is gaining attention understanding the pathogenesis and progression of dysregulated lipid metabolism and inflammation. The Xie Zhuo Tiao Zhi (XZTZ) decoction has been employed in clinical practice for alleviating hyperlipidemia and symptoms related to metabolic disorders. However, the pharmacological mechanisms underlying the effects of XZTZ remain to be elucidated.
PURPOSE
The objective of this study was to examine the pharmacological mechanisms underlying the hypolipidemic and anti-inflammatory effects of XZTZ decoction in a mouse model of NAFLD, as well as the effects of supplementing exogenous metabolites on PO induced cell damage and lipid accumulation in cultured hepatocytes.
METHODS
A high-fat diet (HFD) mouse model was established to examine the effects of XZTZ through oral gavage. The general condition of mice and the protective effect of XZTZ on liver injury were evaluated using histological and biochemical methods. Hematoxylin and eosin staining (H&E) staining and oil red O staining were performed to assess inflammatory and lipid accumulation detection, and cytokine levels were quantitatively analyzed. Additionally, the study included full-length 16S rRNA sequencing, liver transcriptome analysis, and non-targeted metabolomics analysis to investigate the relationship among intestinal microbiome, liver metabolic function, and XZTZ decoction.
RESULTS
XZTZ had a significant impact on the microbial community structure in NAFLD mice. Notably, the abundance of Ileibacterium valens, which was significantly enriched by XZTZ, exhibited a negative correlation with liver injury biomarkers such as, alanine transaminase (ALT) and aspartate transaminase (AST) activity. Moreover, treatment with XZTZ led to a significant enrichment of the purine metabolism pathway in liver tissue metabolites, with inosine, a purine metabolite, showing a significant positive correlation with the abundance of I. valens. XZTZ and inosine also significantly enhanced fatty acid β-oxidation, which led to a reduction in the expression of pro-inflammatory cytokines and the inhibition of liver pyroptosis. These effects contributed to the mitigation of liver injury and hepatocyte damage, both in vivo and vitro. Furthermore, the utilization of HPLC fingerprints and UPLC-Q-TOF-MS elucidated the principal constituents within the XZTZ decoction, including naringin, neohesperidin, atractylenolide III, 23-o-Acetylalisol B, pachymic acid, and ursolic acid which are likely responsible for its therapeutic efficacy. Further investigations are imperative to fully uncover and validate the pharmacodynamic mechanisms underlying these observations.
CONCLUSION
The administration of XZTZ decoction demonstrates a protective effect on the livers of NAFLD mice by inhibiting lipid accumulation and reducing hepatocyte inflammatory damage. This protective effect is mediated by the upregulation of I.valens abundance in the intestine, highlighting the importance of the gut-liver axis. Furthermore, the presesnce of inosine, adenosine, and their derivatives are important in promoting the protective effects of XZTZ. Furthermore, the in vitro approaching, we provide hitherto undocumented evidence indicating that the inosine significantly improves lipid accumulation, inflammatory damage, and pyroptosis in AML12 cells incubated with free fatty acids.
Topics: Animals; Mice; Non-alcoholic Fatty Liver Disease; Gastrointestinal Microbiome; Pyroptosis; RNA, Ribosomal, 16S; Liver; Lipid Metabolism; Diet, High-Fat; Fatty Acids, Nonesterified; Purines; Inosine; Mice, Inbred C57BL
PubMed: 37804819
DOI: 10.1016/j.phymed.2023.155111 -
International Journal of Molecular... May 2023RNA-binding proteins (RBPs) can regulate multiple pathways by binding to RNAs, playing a variety of functions, such as localization, stability, and immunity. In recent... (Review)
Review
RNA-binding proteins (RBPs) can regulate multiple pathways by binding to RNAs, playing a variety of functions, such as localization, stability, and immunity. In recent years, with the development of technology, researchers have discovered that RBPs play a key role in the N6-methyladenosine (m6A) modification process. M6A methylation is the most abundant form of RNA modification in eukaryotes, which is defined as methylation on the sixth N atom of adenine in RNA. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is one of the components of m6A binding proteins, which plays an important role in decoding m6A marks and performing various biological functions. IGF2BP3 is abnormally expressed in many human cancers, often associated with poor prognosis. Here, we summarize the physiological role of IGF2BP3 in organisms and describe its role and mechanism in tumors. These data suggest that IGF2BP3 may be a valuable therapeutic target and prognostic marker in the future.
Topics: Humans; Adenine; Adenosine; Eukaryota; Neoplasms; RNA
PubMed: 37298373
DOI: 10.3390/ijms24119423