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Journal of Materials Chemistry. B Apr 2020DNA methyltransferases are responsible for catalyzing the methylation of adenine/cytosine residues in specific regions of the genome, and they participate in the... (Review)
Review
DNA methyltransferases are responsible for catalyzing the methylation of adenine/cytosine residues in specific regions of the genome, and they participate in the establishment of epigenetic modification patterns. Deregulation of DNA methyltransferase activity will disturb DNA methylation systems, leading to the occurrence of various human diseases including cancers. Moreover, DNA methyltransferases may serve as promising therapeutic targets, and DNA methyltransferase inhibitors have been used for disease treatment. Therefore, the detection of DNA methyltransferases and screening of their inhibitors are crucial for both fundamental biomedical research studies and clinical practice. Due to their excellent size-dependent optical, chemical, electronic, and mechanical features, nanomaterials have been widely used as powerful building materials to construct efficient biosensors for DNA methyltransferase assay with high sensitivity and good selectivity. In this review, we summarize the recent progress in the development of nanomaterial-based biosensors for DNA methyltransferase assay including the strategies, features and applications, and highlight the future direction and challenges in this area as well.
Topics: Biosensing Techniques; DNA Modification Methylases; Humans; Nanostructures; Particle Size; Surface Properties
PubMed: 32095792
DOI: 10.1039/c9tb02458a -
Natural Product Reports Sep 2023Covering: from 2000 up to the very early part of 2023-Adenosyl-L-methionine (SAM) is a naturally occurring trialkyl sulfonium molecule that is typically associated with... (Review)
Review
Covering: from 2000 up to the very early part of 2023-Adenosyl-L-methionine (SAM) is a naturally occurring trialkyl sulfonium molecule that is typically associated with biological methyltransfer reactions. However, SAM is also known to donate methylene, aminocarboxypropyl, adenosyl and amino moieties during natural product biosynthetic reactions. The reaction scope is further expanded as SAM itself can be modified prior to the group transfer such that a SAM-derived carboxymethyl or aminopropyl moiety can also be transferred. Moreover, the sulfonium cation in SAM has itself been found to be critical for several other enzymatic transformations. Thus, while many SAM-dependent enzymes are characterized by a methyltransferase fold, not all of them are necessarily methyltransferases. Furthermore, other SAM-dependent enzymes do not possess such a structural feature suggesting diversification along different evolutionary lineages. Despite the biological versatility of SAM, it nevertheless parallels the chemistry of sulfonium compounds used in organic synthesis. The question thus becomes how enzymes catalyze distinct transformations subtle differences in their active sites. This review summarizes recent advances in the discovery of novel SAM utilizing enzymes that rely on Lewis acid/base chemistry as opposed to radical mechanisms of catalysis. The examples are categorized based on the presence of a methyltransferase fold and the role played by SAM within the context of known sulfonium chemistry.
Topics: S-Adenosylmethionine; Methyltransferases; Catalysis
PubMed: 36891755
DOI: 10.1039/d2np00086e -
Trends in Cancer Jul 2023Numerous strategies are employed by cancer cells to control gene expression and facilitate tumorigenesis. In the study of epitranscriptomics, a diverse set of... (Review)
Review
Numerous strategies are employed by cancer cells to control gene expression and facilitate tumorigenesis. In the study of epitranscriptomics, a diverse set of modifications to RNA represent a new player of gene regulation in disease and in development. N-methyladenosine (mA) is the most common modification on mammalian messenger RNA and tends to be aberrantly placed in cancer. Recognized by a series of reader proteins that dictate the fate of the RNA, mA-modified RNA could promote tumorigenesis by driving protumor gene expression signatures and altering the immunologic response to tumors. Preclinical evidence suggests mA writer, reader, and eraser proteins are attractive therapeutic targets. First-in-human studies are currently testing small molecule inhibition against the methyltransferase-like 3 (METTL3)/methyltransferase-like 14 (METTL14) methyltransferase complex. Additional modifications to RNA are adopted by cancers to drive tumor development and are under investigation.
Topics: Animals; Humans; Methyltransferases; RNA; Methylation; RNA, Messenger; Neoplasms; Carcinogenesis; Mammals
PubMed: 37147166
DOI: 10.1016/j.trecan.2023.04.003 -
Genetics in Medicine : Official Journal... Sep 20235-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the...
PURPOSE
5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive.
METHODS
We combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene.
RESULTS
We identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment.
CONCLUSION
Our data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.
Topics: Humans; Intellectual Disability; Homozygote; Neurodevelopmental Disorders; Methyltransferases; RNA; Pedigree; tRNA Methyltransferases
PubMed: 37226891
DOI: 10.1016/j.gim.2023.100900 -
Cell Communication and Signaling : CCS Nov 2023As one of the most abundant epigenetic modifications in RNA, N-methyladenosine (mA) affects RNA transcription, splicing, stability, and posttranscriptional translation.... (Review)
Review
As one of the most abundant epigenetic modifications in RNA, N-methyladenosine (mA) affects RNA transcription, splicing, stability, and posttranscriptional translation. Methyltransferase-like 3 (METTL3), a key component of the mA methyltransferase complex, dynamically regulates target genes expression through mA modification. METTL3 has been found to play a critical role in tumorigenesis, tumor growth, metastasis, metabolic reprogramming, immune cell infiltration, and tumor drug resistance. As a result, the development of targeted drugs against METTL3 is becoming increasingly popular. This review systematically summarizes the factors that regulate METTL3 expression and explores the specific mechanisms by which METTL3 affects multiple tumor biological behaviors. We aim to provide fundamental support for tumor diagnosis and treatment, at the same time, to offer new ideas for the development of tumor-targeting drugs.
Topics: Methyltransferases; Gene Expression Regulation, Neoplastic; RNA
PubMed: 37996892
DOI: 10.1186/s12964-023-01360-5 -
Molecular Cancer Aug 2022Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine... (Review)
Review
Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine (m6A), the most abundant post-transcriptional modification in eukaryotes, exerts important roles in regulating mRNA metabolism including stability, decay, splicing, transport, and translation. As the key component of the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) catalyzes m6A methylation on mRNA or non-coding RNA to regulate gene expression and cell phenotypes. Dysregulation of METTL14 was deemed to be involved in various aspects of gastrointestinal cancer, such as tumorigenesis, progression, chemoresistance, and metastasis. Plenty of findings have opened up new avenues for exploring the therapeutic potential of gastrointestinal cancer targeting METTL14. In this review, we systematically summarize the recent advances regarding the biological functions of METTL14 in gastrointestinal cancer, discuss its potential clinical applications and propose the research forecast.
Topics: Gastrointestinal Neoplasms; Humans; Methylation; Methyltransferases; RNA; RNA, Messenger
PubMed: 35974338
DOI: 10.1186/s12943-022-01634-5 -
Translational Research : the Journal of... Sep 2023Aberrant N6-methyladenosine (m6A) modification of mRNAs contributes significantly to the epigenetic tumorigenesis, however, its precise role and the key targets in...
Aberrant N6-methyladenosine (m6A) modification of mRNAs contributes significantly to the epigenetic tumorigenesis, however, its precise role and the key targets in osteosarcoma (OS) are not defined. Here we reported that selective METTL3 (methyltransferase like 3) elevation and the consequential increase of m6A modification causally affect OS progression. The fast-growing OS cells displayed preferential upregulation of METTL3 and increased m6A modification. Conversely, m6A inhibition by 3-deazaadenosine, siRNA-mediated METTL3 knockdown or a METTL3-selective inhibitor STM2457 effectively inhibits OS cell growth and induced OS cell apoptosis. Further investigation revealed that an oncogenic protein ZBTB7C was likely a critical m6A target that mediated the oncogenic effects. ZBTB7C mRNA contains a typical m6A motif of high confidence and its mRNA and protein were enriched with increased m6A modification in OS samples/cells. In an OS xenograft model, STM2457 or siRNA-mediated METTL3 knockdown effectively lowed ZBTB7C abundance. More importantly, the anti-OS effects of STM2457 were significantly reduced when ZBTB7C was overexpressed by lentivirus. Together, our results demonstrate that the METTL3 aberration and the resultant ZBTB7C m6A modification form an important epigenetic regulatory loop that promotes OS progression, and targeting the METTL3/ZBTB7C axis may provide novel insights into the potential strategies for OS therapy.
Topics: Humans; Intracellular Signaling Peptides and Proteins; Methyltransferases; Osteosarcoma; RNA, Messenger; RNA, Small Interfering
PubMed: 37121538
DOI: 10.1016/j.trsl.2023.04.005 -
Biomolecules Sep 2020Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has... (Review)
Review
Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has long been recognized as a major global health concern. Arsenic exposure causes changes in skin color and lesions, and more severe health conditions such as black foot disease as well as various cancers originating in the lungs, skin, and bladder. In order to efficiently metabolize and excrete arsenic, it is methylated to monomethylarsonic and dimethylarsinic acid. One single enzyme, arsenic methyltransferase (AS3MT) is responsible for generating both metabolites. AS3MT has been purified from several mammalian and nonmammalian species, and its mRNA sequences were determined from amino acid sequences. With the advent of genome technology, mRNA sequences of have been predicted from many species throughout the animal kingdom. Horizontal gene transfer had been postulated for this gene through phylogenetic studies, which suggests the importance of this gene in appropriately handling arsenic exposures in various organisms. An altered ability to methylate arsenic is dependent on specific single nucleotide polymorphisms (SNPs) in AS3MT. Reduced AS3MT activity resulting in poor metabolism of iAs has been shown to reduce expression of the tumor suppressor gene, , which is a potential pathway in arsenic carcinogenesis. Arsenic is also known to induce oxidative stress in cells. However, the presence of antioxidant response elements (AREs) in the promoter sequences of in several species does not correlate with the ability to methylate arsenic. ARE elements are known to bind NRF2 and induce antioxidant enzymes to combat oxidative stress. NRF2 may be partly responsible for the biotransformation of iAs and the generation of methylated arsenic species via AS3MT. In this article, arsenic metabolism, excretion, and toxicity, a discussion of the gene and its evolutionary history, and DNA methylation resulting from arsenic exposure have been reviewed.
Topics: Animals; Arsenic; Cysteine; Humans; Methylation; Methyltransferases; Phylogeny; Polymorphism, Single Nucleotide; Water Pollutants, Chemical
PubMed: 32971865
DOI: 10.3390/biom10091351 -
Birth Defects Research Nov 2023Kabuki syndrome type 1 (KS1), a rare multisystem congenital disorder, presents with characteristic facial features, intellectual disability, persistent fetal fingertip... (Review)
Review
BACKGROUND
Kabuki syndrome type 1 (KS1), a rare multisystem congenital disorder, presents with characteristic facial features, intellectual disability, persistent fetal fingertip pads, skeletal abnormalities, and postnatal growth delays. KS1 results from pathogenic variants in the KMT2D gene, which encodes a histone methyltransferase protein involved in chromatin remodeling, promoter and enhancer regulation, and scaffold formation during early development. KMT2D also mediates cell signaling pathways, responding to external stimuli and organizing effector protein assembly. Research on KMT2D's molecular mechanisms in KS1 has primarily focused on its histone methyltransferase activity, leaving a gap in understanding the methyltransferase-independent roles in KS1 clinical manifestations.
METHODS
This scoping review examines KMT2D's role in gene expression regulation across various species, cell types, and contexts. We analyzed human pathogenic KMT2D variants using publicly available databases and compared them to research organism models of KS1. We also conducted a systematic search of healthcare and governmental databases for clinical trials, studies, and therapeutic approaches.
RESULTS
Our review highlights KMT2D's critical roles beyond methyltransferase activity in diverse cellular contexts and conditions. We identified six distinct groups of KMT2D as a cell signaling mediator, including evidence of methyltransferase-dependent and -independent activity. A comprehensive search of the literature, clinical databases, and public registries emphasizes the need for basic research on KMT2D's functional complexity and longitudinal studies of KS1 patients to establish objective outcome measurements for therapeutic development.
CONCLUSION
We discuss how KMT2D's role in translating external cellular communication can partly explain the clinical heterogeneity observed in KS1 patients. Additionally, we summarize the current molecular diagnostic approaches and clinical trials targeting KS1. This review is a resource for patient advocacy groups, researchers, and physicians to support KS1 diagnosis and therapeutic development.
Topics: Humans; Face; Histone Methyltransferases; Methyltransferases; Mutation
PubMed: 37158694
DOI: 10.1002/bdr2.2183 -
Current Medicinal Chemistry 2015Epigenetic research has recently become one of the hotspots in the field of bioscience and drug design. DNA methylation and histone methylation serve a critical function... (Review)
Review
Epigenetic research has recently become one of the hotspots in the field of bioscience and drug design. DNA methylation and histone methylation serve a critical function in influencing gene expression and genome function. The inhibition of DNA and histone methyltransferases (DNMTs and HMTs) is a promising approach for the therapeutic treatment of numerous diseases, including cancer. This work reviews the recent achievements in methyltransferase crystallographic structure resolution and bioactive inhibitor screening. We discuss the features of DNA and HMT structures, as well as the mechanism and structure-function relationship of transferase inhibitors, to elucidate how methyltransferase and inhibitor interactions occur both internally and externally. This study briefly reviews the biological function, as well as the inhibitor discovery and development, of DNA/histone methyltransferases.
Topics: Animals; DNA (Cytosine-5-)-Methyltransferases; Enzyme Inhibitors; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Protein Binding
PubMed: 25386815
DOI: 10.2174/0929867321666141106114538