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Journal of Experimental & Clinical... Apr 2021The N6-methyladenosine (m6A) modification is a dynamic and reversible epigenetic modification, which is co-transcriptionally deposited by a methyltransferase complex,... (Review)
Review
The N6-methyladenosine (m6A) modification is a dynamic and reversible epigenetic modification, which is co-transcriptionally deposited by a methyltransferase complex, removed by a demethylase, and recognized by reader proteins. Mechanistically, m6A modification regulates the expression levels of mRNA and nocoding RNA by modulating the fate of modified RNA molecules, such as RNA splicing, nuclear transport, translation, and stability. Several studies have shown that m6A modification is dysregulated in the progression of multiple diseases, especially human tumors. We emphasized that the dysregulation of m6A modification affects different signal transduction pathways and involves in the biological processes underlying tumor cell proliferation, apoptosis, invasion and migration, and metabolic reprogramming, and discuss the effects on different cancer treatment.
Topics: Adenosine; Disease Progression; Humans; Neoplasms; Signal Transduction
PubMed: 33926508
DOI: 10.1186/s13046-021-01952-4 -
Organic & Biomolecular Chemistry Apr 2024Hypochlorous acid (HOCl) released from activated leukocytes plays a significant role in the human immune system, but is also implicated in numerous diseases due to its...
Hypochlorous acid (HOCl) released from activated leukocytes plays a significant role in the human immune system, but is also implicated in numerous diseases due to its inappropriate production. Chlorinated nucleobases induce genetic changes that potentially enable and stimulate carcinogenesis, and thus have attracted considerable attention. However, their multiple halogenation sites pose challenges to identify them. As a good complement to experiments, quantum chemical computation was used to uncover chlorination sites and chlorinated products in this study. The results indicate that anion salt forms of all purine compounds play significant roles in chlorination except for adenosine. The kinetic reactivity order of all reaction sites in terms of the estimated apparent rate constant (in M s) is heterocyclic NH/N (10-10) > exocyclic NH (10-10) > heterocyclic C8 (10-10), but the order is reversed for thermodynamics. Combining kinetics and thermodynamics, the numerical simulation results show that N9 is the most reactive site for purine bases to form the main initial chlorinated product, while for purine nucleosides N1 and exocyclic / are the most reactive sites to produce the main products controlled by kinetics and thermodynamics, respectively, and C8 is a possible site to generate the minor product. The formation mechanisms of biomarker 8-Cl- and 8-oxo-purine derivatives were also investigated. Additionally, the structure-kinetic reactivity relationship study reveals a good correlation between lg and APT charge in all purine compounds compared to FED (HOMO), which proves again that the electrostatic interaction plays a key role. The results are helpful to further understand the reactivity of various reaction sites in aromatic compounds during chlorination.
Topics: Humans; Nucleosides; Halogenation; Catalytic Domain; Purine Nucleosides; Hypochlorous Acid; Kinetics; Chlorine; Water Pollutants, Chemical
PubMed: 38516867
DOI: 10.1039/d3ob02111d -
Methods in Molecular Biology (Clifton,... 2021Following A-to-I editing of double-stranded RNA (dsRNA) molecules, sequencing reactions interpret the edited inosine (I) as guanosine (G). For this reason, current...
Following A-to-I editing of double-stranded RNA (dsRNA) molecules, sequencing reactions interpret the edited inosine (I) as guanosine (G). For this reason, current methods to detect A-to-I editing sites work to align RNA sequences to their reference DNA sequence in order to reveal A-to-G mismatches. However, areas with heavily edited reads produce dense clusters of A-to-G mismatches that hinder alignment, and complicate correct identification of the sites. The presented approach employs prudent alignment and examination of excessive mismatch events, enabling high-accuracy detection of hyper-edited reads and sites.
Topics: Adenosine; Animals; Base Sequence; Humans; Inosine; RNA Editing; RNA, Double-Stranded; Sequence Analysis, RNA
PubMed: 32729083
DOI: 10.1007/978-1-0716-0787-9_13 -
Endocrine, Metabolic & Immune Disorders... 2022N6-methyladenosine (m6A) is a prevalent modification of RNA in eukaryotes, bacteria, and viruses. It is highly conserved and can affect the structure, localization, and... (Review)
Review
N6-methyladenosine (m6A) is a prevalent modification of RNA in eukaryotes, bacteria, and viruses. It is highly conserved and can affect the structure, localization, and biology functions of RNA. In recent years, multiple m6A methylation sites have been identified in the viral RNA genome and transcripts of DNA viruses. This modification occurs commonly during the primary infection and is dynamically regulated by a methyltransferase (writers), demethylase (eraser) and m6A-binding proteins (readers) within the host cells. The abnormal m6A modification not only affects the replication of pathogenic viruses and host immune response but also contributes to the pathogenesis of virus-induced cancers. In this review, we highlight recent advances on the mechanism of m6A modification on viral replication, host immune response and carcinogenesis to provide a novel insight for epigenetic prevention of viral infection and virus-driven carcinogenesis.
Topics: Adenosine; Carcinogenesis; Humans; RNA; Virus Diseases; Viruses
PubMed: 35418293
DOI: 10.2174/2772432817666220412112759 -
Molecules (Basel, Switzerland) Sep 2020An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of -heterocycle (purine...
An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of -heterocycle (purine nucleobase) with acetal (cyclic or acyclic, variously branched) and anhydride (preferentially acetic anhydride). The procedure employs cheap and easily available acetals, acetic anhydride, and trimethylsilyl trifluoromethanesulfonate (TMSOTf). The multi-component reaction is carried out in acetonitrile at room temperature for 15 min and provides moderate to high yields (up to 88%) of diverse acyclonucleosides branched at the aliphatic side chain. The procedure exhibits a broad substrate scope of -heterocycles and acetals, and, in the case of purine derivatives, also excellent regioselectivity, giving almost exclusively -9 isomers.
Topics: Acetals; Acetic Anhydrides; Alkylation; Lewis Acids; Mesylates; Purine Nucleosides; Solvents; Stereoisomerism
PubMed: 32961820
DOI: 10.3390/molecules25184307 -
Biopolymers Jan 2021The notion of using synthetic heterocycles instead of the native bases to interface with DNA and RNA has been explored for nearly 60 years. Unnatural bases compatible... (Review)
Review
The notion of using synthetic heterocycles instead of the native bases to interface with DNA and RNA has been explored for nearly 60 years. Unnatural bases compatible with the DNA/RNA coding interface have the potential to expand the genetic code and co-opt the machinery of biology to access new macromolecular function; accordingly, this body of research is core to synthetic biology. While much of the literature on artificial bases focuses on code expansion, there is a significant and growing effort on docking synthetic heterocycles to noncoding nucleic acid interfaces; this approach seeks to illuminate major processes of nucleic acids, including regulation of transcription, translation, transport, and transcript lifetimes. These major avenues of research at the coding and noncoding interfaces have in common fundamental principles in molecular recognition. Herein, we provide an overview of foundational literature in biophysics of base recognition and unnatural bases in coding to provide context for the developing area of targeting noncoding nucleic acid interfaces with synthetic bases, with a focus on systems developed through iterative design and biophysical study.
Topics: Base Pairing; DNA; Hydrogen Bonding; Purine Nucleosides; Pyrimidine Nucleosides; RNA; Synthetic Biology
PubMed: 32969496
DOI: 10.1002/bip.23399 -
The Journal of Biological Chemistry Aug 2021N-methyladenosine (mA) is the most frequent chemical modification in eukaryotic mRNA and is known to participate in a variety of physiological processes, including... (Review)
Review
N-methyladenosine (mA) is the most frequent chemical modification in eukaryotic mRNA and is known to participate in a variety of physiological processes, including cancer progression and viral infection. The reversible and dynamic mA modification is installed by mA methyltransferase (writer) enzymes and erased by mA demethylase (eraser) enzymes. mA modification recognized by mA binding proteins (readers) regulates RNA processing and metabolism, leading to downstream biological effects such as promotion of stability and translation or increased degradation. The mA writers and erasers determine the abundance of mA modifications and play decisive roles in its distribution and function. In this review, we focused on mA writers and erasers and present an overview on their known functions and enzymatic molecular mechanisms, showing how they recognize substrates and install or remove mA modifications. We also summarize the current applications of mA writers and erasers for mA detection and highlight the merits and drawbacks of these available methods. Lastly, we describe the biological functions of mA in cancers and viral infection based on research of mA writers and erasers and introduce new assays for mA functionality via programmable mA editing tools.
Topics: Adenosine; Eukaryotic Cells; Humans; Methyltransferases; Neoplasms; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 34280435
DOI: 10.1016/j.jbc.2021.100973 -
Biomolecules Dec 2020Tricyclic wyosine derivatives are present at position 37 in tRNA of both eukaryotes and archaea. In eukaryotes, five different enzymes are needed to form a final... (Review)
Review
Tricyclic wyosine derivatives are present at position 37 in tRNA of both eukaryotes and archaea. In eukaryotes, five different enzymes are needed to form a final product, wybutosine (yW). In archaea, 4-demethylwyosine (imG-14) is an intermediate for the formation of three different wyosine derivatives, yW-72, imG, and mimG. In this review, current knowledge regarding the archaeal enzymes involved in this process and their reaction mechanisms are summarized. The experiments aimed to elucidate missing steps in biosynthesis pathways leading to the formation of wyosine derivatives are suggested. In addition, the chemical synthesis pathways of archaeal wyosine nucleosides are discussed, and the scheme for the formation of yW-86 and yW-72 is proposed. Recent data demonstrating that wyosine derivatives are present in the other tRNA species than those specific for phenylalanine are discussed.
Topics: Archaea; Guanosine; RNA, Transfer
PubMed: 33276555
DOI: 10.3390/biom10121627 -
Journal of the American Chemical Society Oct 2022A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C-H functionalization of...
A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C-H functionalization of diverse (hetero)aromatics with dibenzothiophene--oxide followed by the Negishi cross-cooupling with bis(4,6-dichloropyrimidin-5-yl)zinc. This cross-coupling afforded a series of (het)aryl-pyrimidines that were converted to fused deazapurine heterocycles through azidation and thermal cyclization. The fused heterocycles were glycosylated to the corresponding 2'-deoxy- and ribonucleosides, and a series of derivatives were prepared by nucleophilic substitutions at position 4. Four series of new polycyclic thieno-fused 7-deazapurine nucleosides were synthesized using this strategy. Most of the deoxyribonucleosides showed good cytotoxic activity, especially for the CCRF-CEM cell line. Phenyl- and thienyl-substituted thieno-fused 7-deazapurine nucleosides were fluorescent, and the former one was converted to 2'-deoxyribonucleoside triphosphate for enzymatic synthesis of labeled oligonucleotides.
Topics: Nucleosides; Cell Line, Tumor; Ribonucleosides; Pyrimidines; Oxides; Zinc; Oligonucleotides; Deoxyribonucleosides; Purine Nucleosides
PubMed: 36245092
DOI: 10.1021/jacs.2c07517 -
Advances in Biological Regulation Jan 2023Reversible N6-methyladenosine (mA) RNA modification is a posttranscriptional epigenetic modification of the RNA that regulates many key aspects of RNA metabolism and... (Review)
Review
Reversible N6-methyladenosine (mA) RNA modification is a posttranscriptional epigenetic modification of the RNA that regulates many key aspects of RNA metabolism and function. In this review, we highlight major recent advances in the field, with special emphasis on the potential link between mA modifications and RNA structure. We will also discuss the role of RNA methylation of neuronal transcripts, and the emerging evidence of a potential role in RNA transport and local translation in dendrites and axons of transcripts involved in synaptic functions and axon growth.
Topics: Humans; Methylation; RNA, Messenger; Epigenesis, Genetic; Adenosine; Protein Processing, Post-Translational
PubMed: 36513580
DOI: 10.1016/j.jbior.2022.100926