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Genomics, Proteomics & Bioinformatics Aug 2023N-methyladenine (mA) is the most abundant RNA modification in mammalian messenger RNAs (mRNAs), which participates in and regulates many important biological activities,... (Review)
Review
N-methyladenine (mA) is the most abundant RNA modification in mammalian messenger RNAs (mRNAs), which participates in and regulates many important biological activities, such as tissue development and stem cell differentiation. Due to an improved understanding of mA, researchers have discovered that the biological function of mA can be linked to many stages of mRNA metabolism and that mA can regulate a variety of complex biological processes. In addition to its location on mammalian mRNAs, mA has been identified on viral transcripts. mA also plays important roles in the life cycle of many viruses and in viral replication in host cells. In this review, we briefly introduce the detection methods of mA, the mA-related proteins, and the functions of mA. We also summarize the effects of mA-related proteins on viral replication and infection. We hope that this review provides researchers with some insights for elucidating the complex mechanisms of the epitranscriptome related to viruses, and provides information for further study of the mechanisms of other modified nucleobases acting on processes such as viral replication. We also anticipate that this review can stimulate collaborative research from different fields, such as chemistry, biology, and medicine, and promote the development of antiviral drugs and vaccines.
Topics: Animals; Viruses; RNA, Messenger; Adenosine; Cell Differentiation; Mammals
PubMed: 35835441
DOI: 10.1016/j.gpb.2022.04.009 -
Cancer Medicine Oct 2023CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved-daratumumab and isatuximab.... (Review)
Review
BACKGROUND
CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved-daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.
AIM
Among the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38-mediated T-cell activation. Patients who respond to anti-CD38 targeting treatment experience more marked changes in T-cell expansion, activity, and clonality than nonresponders.
IMPLICATIONS
Resistance mechanisms that undermine the immunomodulatory effects of CD38-targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment-related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T-cell engagers.
Topics: Humans; Multiple Myeloma; ADP-ribosyl Cyclase 1; Immunomodulation; Immunologic Factors; Adenosine; Tumor Microenvironment
PubMed: 37840445
DOI: 10.1002/cam4.6619 -
International Journal of Molecular... Jul 2023The search for new and effective treatment targets for cancer immunotherapy is an ongoing challenge. Alongside the more established inhibitory immune checkpoints, a... (Review)
Review
The search for new and effective treatment targets for cancer immunotherapy is an ongoing challenge. Alongside the more established inhibitory immune checkpoints, a novel potential target is CD73. As one of the key enzymes in the purinergic signalling pathway CD73 is responsible for the generation of immune suppressive adenosine. The expression of CD73 is higher in tumours than in the corresponding healthy tissues and associated with a poor prognosis. CD73, mainly by the production of adenosine, is critical in the suppression of an adequate anti-tumour immune response, but also in promoting cancer cell proliferation, tumour growth, angiogenesis, and metastasis. The upregulation of CD73 and generation of adenosine by tumour or tumour-associated immune cells is a common resistance mechanism to many cancer treatments such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Therefore, the inhibition of CD73 represents a new and promising approach to increase therapy efficacy. Several CD73 inhibitors have already been developed and successfully demonstrated anti-cancer activity in preclinical studies. Currently, clinical studies evaluate CD73 inhibitors in different therapy combinations and tumour entities. The initial results suggest that inhibiting CD73 could be an effective option to augment anti-cancer immunotherapeutic strategies. This review provides an overview of the rationale behind the CD73 inhibition in different treatment combinations and the role of CD73 as a prognostic marker.
Topics: Humans; 5'-Nucleotidase; Adenosine; Clinical Relevance; Immunosuppression Therapy; Immunotherapy; Neoplasms
PubMed: 37511518
DOI: 10.3390/ijms241411759 -
Autoimmunity Dec 2023Skin diseases are global health issues caused by multiple pathogenic factors, in which epigenetics plays an invaluable role. Post-transcriptional RNA modifications are... (Review)
Review
Skin diseases are global health issues caused by multiple pathogenic factors, in which epigenetics plays an invaluable role. Post-transcriptional RNA modifications are important epigenetic mechanism that regulate gene expression at the genome-wide level. N6-methyladenosine (m6A) is the most prevalent modification that occurs in the messenger RNAs (mRNA) of most eukaryotes, which is installed by methyltransferases called "writers", removed by demethylases called "erasers", and recognised by RNA-binding proteins called "readers". To date, m6A is emerging to play essential part in both physiological processes and pathological progression, including skin diseases. However, a systematic summary of m6A in skin disease has not yet been reported. This review starts by illustrating each m6A-related modifier specifically and their roles in RNA processing, and then focus on the existing research advances of m6A in immune homeostasis and skin diseases.
Topics: Humans; Adenosine; Methylation; Methyltransferases; RNA; RNA, Messenger; Skin Diseases
PubMed: 36708146
DOI: 10.1080/08916934.2023.2167983 -
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 -
Biomedicine & Pharmacotherapy =... Apr 2024Hepatocellular carcinoma (HCC) is one of the deadliest cancers of human, the tumor-related death of which ranks third among the common malignances. N-methyladenosine... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the deadliest cancers of human, the tumor-related death of which ranks third among the common malignances. N-methyladenosine (mA) methylation, the most abundant internal modification of RNA in mammals, participates in the metabolism of mRNA and interrelates with ncRNAs. In this paper, we overviewed the complex function of mA regulators in HCC, including regulating the tumorigenesis, progression, prognosis, stemness, metabolic reprogramming, autophagy, ferroptosis, drug resistance and tumor immune microenvironment (TIME). Furthermore, we elucidated the interplay between mA modification and non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Finally, we summarized the potential of mA regulators as diagnostic biomarkers. What's more, we reviewed the inhibitors targeting mA enzymes as promising therapeutic targets of HCC. We aimed to help understand the function of mA methylation in HCC systematically and comprehensively so that more effective strategies for HCC treatment will be developed.
Topics: Humans; Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Adenosine; MicroRNAs; Mammals; Tumor Microenvironment
PubMed: 38452654
DOI: 10.1016/j.biopha.2024.116365 -
Theranostics 2024The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can...
The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can induce cellular senescence. Cellular interactions are widespread in the TME, and tumor cells reprogram immune cells metabolically by producing metabolites. However, how senescent cells remodel the metabolism of TME remains unclear. This study aimed to explore precise targets to enhance senescent cells-induced anti-tumor immunity from a metabolic perspective. The senescence model was induced by 8 Gy×3 radiotherapy or cisplatin chemotherapy, and the model was induced by 10 Gy-irradiation or cisplatin treatment. Metabonomic analysis and ELISA assay on tumor interstitial fluid were performed for metabolites screening. Marker expression and immune cell infiltration in the TME were analyzed by flow cytometry. Cell co-culture system and senescence-conditioned medium were used for crosstalk validation . RNA sequencing and rescue experiments were conducted for mechanism excavation. Immunofluorescence staining and single-cell transcriptome profiling analysis were performed for clinical validation. We innovatively reveal the metabolic landscape of the senescent TME, characterized with the elevation of adenosine. It is attributed to the senescent tumor cell-induced CD73 upregulation of tumor-associated macrophages (TAMs). CD73 expression in TAMs is evoked by SASP-related pro-inflammatory cytokines, especially IL-6, and regulated by JAK/STAT3 pathway. Consistently, a positive correlation between tumor cells senescence and TAMs CD73 expression is identified in lung cancer clinical specimens and databases. Lastly, blocking CD73 in a senescent background suppresses tumors and activates CD8 T cell-mediated antitumor immunity. TAMs expressed CD73 contributes significantly to the adenosine accumulation in the senescent TME, suggesting targeting CD73 is a novel synergistic anti-tumor strategy in the aging microenvironment.
Topics: Humans; Tumor Microenvironment; Cisplatin; Macrophages; Cellular Senescence; Lung Neoplasms; Adenosine
PubMed: 38323313
DOI: 10.7150/thno.91119 -
Frontiers in Immunology 2023Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms... (Review)
Review
Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.
Topics: Humans; Multiple Sclerosis; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Cladribine; Central Nervous System Diseases
PubMed: 38162670
DOI: 10.3389/fimmu.2023.1290666 -
Frontiers in Endocrinology 2023The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression... (Review)
Review
The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N-methyladenosine (mA) and N,2'-O-dimethyladenosine (mAm) are among the most prevalent and well-characterized modified nucleosides in eukaryotic RNA. Both of these modifications are dynamically regulated by a complex set of epitranscriptomic regulators called writers, readers, and erasers. Altered levels of mA and also several regulatory proteins were already associated with diabetic tissues. This review summarizes the current knowledge and gaps about mA and mAm modifications and their respective regulators in the pathophysiology of diabetes mellitus. It focuses mainly on the more prevalent type 2 diabetes mellitus (T2DM) and its treatment by metformin, the first-line antidiabetic agent. A better understanding of epitranscriptomic modifications in this highly prevalent disease deserves further investigation and might reveal clinically relevant discoveries in the future.
Topics: Humans; RNA, Messenger; Diabetes Mellitus, Type 2; Adenosine; RNA; RNA Processing, Post-Transcriptional
PubMed: 37484960
DOI: 10.3389/fendo.2023.1223583 -
Genes Aug 2023Fatty liver disease is one of the major causes of morbidity and mortality worldwide. Fatty liver includes non-alcoholic fatty liver disease (NAFLD) and non-alcoholic... (Review)
Review
Fatty liver disease is one of the major causes of morbidity and mortality worldwide. Fatty liver includes non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), now replaced by a consensus group as metabolic dysfunction-associated steatotic liver disease (MASLD). While excess nutrition and obesity are major contributors to fatty liver, the underlying mechanisms remain largely unknown and therapeutic interventions are limited. Reversible chemical modifications in RNA are newly recognized critical regulators controlling post-transcriptional gene expression. Among these modifications, N6-methyladenosine (m6A) is the most abundant and regulates transcript abundance in fatty liver disease. Modulation of m6A by readers, writers, and erasers (RWE) impacts mRNA processing, translation, nuclear export, localization, and degradation. While many studies focus on m6A RWE expression in human liver pathologies, limitations of technology and bioinformatic methods to detect m6A present challenges in understanding the epitranscriptomic mechanisms driving fatty liver disease progression. In this review, we summarize the RWE of m6A and current methods of detecting m6A in specific genes associated with fatty liver disease.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Adenosine; Computational Biology; Nutritional Status
PubMed: 37628704
DOI: 10.3390/genes14081653