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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 -
Mini Reviews in Medicinal Chemistry 2018Since 1929, several researchers have conducted studies in relation to the nucleoside of adenosine (1) mainly distribution identifying, characterizing their biological... (Review)
Review
Since 1929, several researchers have conducted studies in relation to the nucleoside of adenosine (1) mainly distribution identifying, characterizing their biological importance and synthetic chemistry to which this type of molecule has been subjected to obtain multiple of its derivatives. The receptors that interact with adenosine and its derivatives, called purinergic receptors, are classified as A1, A2A, A2B and A3. In the presence of agonists and antagonists, these receptors are involved in various physiological processes and diseases. This review describes and compares some of the synthetic methods that have been developed over the last 30 years for obtaining some adenosine derivatives, classified according to substitution processes, complexation, mating and conjugation. Finally, we mention that although the concentrations of these nucleosides are low in normal tissues, they can increase rapidly in pathophysiological conditions such as hypoxia, ischemia, inflammation, trauma and cancer. In particular, the evaluation of adenosine derivatives as adjunctive therapy promises to have a significant impact on the treatment of certain cancers, although the transfer of these results to clinical practice requires a deeper understanding of how adenosine regulates the process of tumorigenesis.
Topics: Adenosine; Antineoplastic Agents; Aza Compounds; Brain Neoplasms; Glioblastoma; Humans; Receptors, Purinergic P1; Sulfonic Acids
PubMed: 29769005
DOI: 10.2174/1389557518666180516163539 -
Accounts of Chemical Research Oct 2023The function of cellular RNA is modulated by a host of post-transcriptional chemical modifications installed by dedicated RNA-modifying enzymes. RNA modifications are...
The function of cellular RNA is modulated by a host of post-transcriptional chemical modifications installed by dedicated RNA-modifying enzymes. RNA modifications are widespread in biology, occurring in all kingdoms of life and in all classes of RNA molecules. They regulate RNA structure, folding, and protein-RNA interactions, and have important roles in fundamental gene expression processes involving mRNA, tRNA, rRNA, and other types of RNA species. Our understanding of RNA modifications has advanced considerably; however, there are still many outstanding questions regarding the distribution of modifications across all RNA transcripts and their biological function. One of the major challenges in the study of RNA modifications is the lack of sequencing methods for the transcriptome-wide mapping of different RNA-modification structures. Furthermore, we lack general strategies to characterize RNA-modifying enzymes and RNA-modification reader proteins. Therefore, there is a need for new approaches to enable integrated studies of RNA-modification chemistry and biology.In this Account, we describe our development and application of chemoproteomic strategies for the study of RNA-modification-associated proteins. We present two orthogonal methods based on nucleoside and oligonucleotide chemical probes: 1) RNA-mediated activity-based protein profiling (RNABPP), a metabolic labeling strategy based on reactive modified nucleoside probes to profile RNA-modifying enzymes in cells and 2) photo-cross-linkable diazirine-containing synthetic oligonucleotide probes for identifying RNA-modification reader proteins.We use RNABPP with C5-modified cytidine and uridine nucleosides to capture diverse RNA-pyrimidine-modifying enzymes including methyltransferases, dihydrouridine synthases, and RNA dioxygenase enzymes. Metabolic labeling facilitates the mechanism-based cross-linking of RNA-modifying enzymes with their native RNA substrates in cells. Covalent RNA-protein complexes are then isolated by denaturing oligo(dT) pulldown, and cross-linked proteins are identified by quantitative proteomics. Once suitable modified nucleosides have been identified as mechanism-based proteomic probes, they can be further deployed in transcriptome-wide sequencing experiments to profile the substrates of RNA-modifying enzymes at nucleotide resolution. Using 5-fluorouridine-mediated RNA-protein cross-linking and sequencing, we analyzed the substrates of human dihydrouridine synthase DUS3L. 5-Ethynylcytidine-mediated cross-linking enabled the investigation of ALKBH1 substrates. We also characterized the functions of these RNA-modifying enzymes in human cells by using genetic knockouts and protein translation reporters.We profiled RNA readers for -methyladenosine (mA) and -methyladenosine (mA) using a comparative proteomic workflow based on diazirine-containing modified oligonucleotide probes. Our approach enables quantitative proteome-wide analysis of the preference of RNA-binding proteins for modified nucleotides across a range of affinities. Interestingly, we found that YTH-domain proteins YTHDF1/2 can bind to both mA and mA to mediate transcript destabilization. Furthermore, mA also inhibits stress granule proteins from binding to RNA.Taken together, we demonstrate the application of chemical probing strategies, together with proteomic and transcriptomic workflows, to reveal new insights into the biological roles of RNA modifications and their associated proteins.
Topics: Humans; Nucleosides; Adenosine; Proteomics; Diazomethane; Oligonucleotide Probes; RNA; AlkB Homolog 1, Histone H2a Dioxygenase
PubMed: 37733063
DOI: 10.1021/acs.accounts.3c00450 -
Molecules and Cells Jul 2022In response to environmental changes, signaling pathways rewire gene expression programs through transcription factors. Epigenetic modification of the transcribed RNA... (Review)
Review
In response to environmental changes, signaling pathways rewire gene expression programs through transcription factors. Epigenetic modification of the transcribed RNA can be another layer of gene expression regulation. -adenosine methylation (mA) is one of the most common modifications on mRNA. It is a reversible chemical mark catalyzed by the enzymes that deposit and remove methyl groups. mA recruits effector proteins that determine the fate of mRNAs through changes in splicing, cellular localization, stability, and translation efficiency. Emerging evidence shows that key signal transduction pathways including TGFβ (transforming growth factor-β), ERK (extracellular signal-regulated kinase), and mTORC1 (mechanistic target of rapamycin complex 1) regulate downstream gene expression through mA processing. Conversely, mA can modulate the activity of signal transduction networks via mA modification of signaling pathway genes or by acting as a ligand for receptors. In this review, we discuss the current understanding of the crosstalk between mA and signaling pathways and its implication for biological systems.
Topics: Adenosine; Mechanistic Target of Rapamycin Complex 1; Methylation; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta
PubMed: 35748227
DOI: 10.14348/molcells.2022.0017 -
Journal of Hematology & Oncology May 2024As the most common form of epigenetic regulation by RNA, N methyladenosine (mA) modification is closely involved in physiological processes, such as growth and... (Review)
Review
As the most common form of epigenetic regulation by RNA, N methyladenosine (mA) modification is closely involved in physiological processes, such as growth and development, stem cell renewal and differentiation, and DNA damage response. Meanwhile, its aberrant expression in cancer tissues promotes the development of malignant tumors, as well as plays important roles in proliferation, metastasis, drug resistance, immunity and prognosis. This close association between mA and cancers has garnered substantial attention in recent years. An increasing number of small molecules have emerged as potential agents to target mA regulators for cancer treatment. These molecules target the epigenetic level, enabling precise intervention in RNA modifications and efficiently disrupting the survival mechanisms of tumor cells, thus paving the way for novel approaches in cancer treatment. However, there is currently a lack of a comprehensive review on small molecules targeting mA regulators for anti-tumor. Here, we have comprehensively summarized the classification and functions of mA regulators, elucidating their interactions with the proliferation, metastasis, drug resistance, and immune responses in common cancers. Furthermore, we have provided a comprehensive overview on the development, mode of action, pharmacology and structure-activity relationships of small molecules targeting mA regulators. Our aim is to offer insights for subsequent drug design and optimization, while also providing an outlook on future prospects for small molecule development targeting mA.
Topics: Animals; Humans; Adenosine; Antineoplastic Agents; Epigenesis, Genetic; Neoplasms; Small Molecule Libraries
PubMed: 38711100
DOI: 10.1186/s13045-024-01546-5 -
Cancer Science Aug 2019Precision medicine places significant emphasis on techniques for the identification of DNA mutations and gene expression by deep sequencing of gene panels to obtain... (Review)
Review
Precision medicine places significant emphasis on techniques for the identification of DNA mutations and gene expression by deep sequencing of gene panels to obtain medical data. However, other diverse information that is not easily readable using bioinformatics, including RNA modifications, has emerged as a novel diagnostic and innovative therapy owing to its multifunctional aspects. It is suggested that this breakthrough innovation might open new avenues for the elucidation of uncharacterized cancer cellular functions to develop more precise medical applications. The functional characteristics and regulatory mechanisms of RNA modifications, ie, the epitranscriptome (ETR), which reflects RNA metabolism, remains unclear, mainly due to detection methods being limited. Recent studies have revealed that N6-methyl adenosine, the most common modification in mRNA in eukaryotes, is affected in various types of cancer and, in some cases, cancer stem cells, but also affects cellular responses to viral infections. The ETR can control cancer cell fate through mRNA splicing, stability, nuclear export, and translation. Here we report on the recent progress of ETR detection methods, and biological findings regarding the significance of ETR in cancer precision medicine.
Topics: Adenosine; Animals; Eukaryota; Humans; Neoplasms; Precision Medicine; RNA, Messenger; Transcriptome
PubMed: 31187550
DOI: 10.1111/cas.14095 -
Current Opinion in Genetics &... Feb 2018As the most abundant internal modification in eukaryotic messenger RNAs identified, N-methyladenosine (mA) has been shown recently to play essential roles in various... (Review)
Review
As the most abundant internal modification in eukaryotic messenger RNAs identified, N-methyladenosine (mA) has been shown recently to play essential roles in various normal bioprocesses. Evidence is emerging that mA modification and its regulatory proteins also play critical roles in various cancers including leukemia, brain tumor, breast cancer and lung cancer, etc. For instance, FTO, the first mA demethylase identified, has been reported recently to play an oncogenic role in leukemia and glioblastoma. ALKBH5 (another mA demethylase) has been reported to exert a tumor-promoting function in glioblastoma and breast cancer. METTL3 (a major mA methyltransferase) likely plays distinct roles between glioblastoma and lung cancer. Here we discuss the recent progress and future prospects in study of mA machinery in cancer.
Topics: Adenosine; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Gene Expression Regulation, Neoplastic; Neoplasms; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 29040886
DOI: 10.1016/j.gde.2017.10.005 -
Signal Transduction and Targeted Therapy Apr 2022Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in the genetic material without any... (Review)
Review
Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes. Epigenetic modifications regulate many biological processes, such as growth, aging, and various diseases, including cancer. With the advancement of next-generation sequencing technology, the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research. This review studied several common RNA modifications, such as N-methyladenosine, 5-methylcytosine, and pseudouridine. The deposition and roles of these modifications in coding and noncoding RNAs are summarized in detail. Based on the RNA modification background, this review summarized the expression, function, and underlying molecular mechanism of these modifications and their regulators in cancer and further discussed the role of some existing small-molecule inhibitors. More in-depth studies on RNA modification and cancer are needed to broaden the understanding of epigenetics and cancer diagnosis, treatment, and prognosis.
Topics: 5-Methylcytosine; Adenosine; Humans; Neoplasms; Pseudouridine; RNA Processing, Post-Transcriptional; RNA, Untranslated
PubMed: 35484099
DOI: 10.1038/s41392-022-01003-0 -
Journal of Hematology & Oncology Jul 2021N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects... (Review)
Review
N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.
Topics: Adenosine; Animals; Gene Expression Regulation, Neoplastic; Humans; Methyltransferases; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 34315512
DOI: 10.1186/s13045-021-01129-8 -
Nucleic Acids Research Feb 2022During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA...
During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate that deposition of N6-methyladenosine (m6A) regulates full-length RNA packaging. While m6A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation promoted the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and contributes to full-length RNA demethylation. We further identified two highly conserved adenosines within the 5'-UTR that have a crucial functional role in m6A methylation and packaging of the full-length RNA. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the HIV-1 full-length RNA molecules that will be used as viral genomes.
Topics: 5' Untranslated Regions; Adenosine; Gene Products, gag; HIV-1; Methylation; RNA, Viral; Virion
PubMed: 35137199
DOI: 10.1093/nar/gkac062