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Ageing Research Reviews Nov 2022Modifications of RNA, collectively called the "epitranscriptome", might provide novel biomarkers and innovative targets for interventions in geroscience but are just... (Review)
Review
Modifications of RNA, collectively called the "epitranscriptome", might provide novel biomarkers and innovative targets for interventions in geroscience but are just beginning to be studied in the context of ageing and stress resistance. RNA modifications modulate gene expression by affecting translation initiation and speed, miRNA binding, RNA stability, and RNA degradation. Nonetheless, the precise underlying molecular mechanisms and physiological consequences of most alterations of the epitranscriptome are still only poorly understood. We here systematically review different types of modifications of rRNA, tRNA and mRNA, the methodology to analyze them, current challenges in the field, and human disease associations. Furthermore, we compiled evidence for a connection between individual enzymes, which install RNA modifications, and lifespan in yeast, worm and fly. We also included resistance to different stressors and competitive fitness as search criteria for genes potentially relevant to ageing. Promising candidates identified by this approach include RCM1/NSUN5, RRP8, and F33A8.4/ZCCHC4 that introduce base methylations in rRNA, the methyltransferases DNMT2 and TRM9/ALKBH8, as well as factors involved in the thiolation or A to I editing in tRNA, and finally the mA machinery for mRNA.
Topics: Aging; AlkB Homolog 8, tRNA Methyltransferase; Animals; Humans; Methyltransferases; MicroRNAs; RNA, Messenger; RNA, Ribosomal; RNA, Transfer; Saccharomyces cerevisiae
PubMed: 35908668
DOI: 10.1016/j.arr.2022.101700 -
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 -
Biochimica Et Biophysica Acta. Reviews... Nov 2023Affected landscape of RNA modifications is frequently observed in different cancer cells that can be associated with the development of cancer cell phenotypic traits... (Review)
Review
Affected landscape of RNA modifications is frequently observed in different cancer cells that can be associated with the development of cancer cell phenotypic traits such as sustained proliferation, migration and invasion, apoptosis resistance and metabolic reprograming. DNMT2/TRDMT1 5-methylcytosine methyltransferase, initially classified as DNA methyltransferase, can methylate both tRNA and mRNA promoting tRNA stability and proper protein synthesis, and orchestrating DNA damage response (DDR) and DNA stability, respectively. TRDMT1 is associated with cancer progression as its levels can be elevated and its mutations can be observed in a number of cancer types. TRDMT1 gene knockout (KO) can sensitize cancer cells of different origin to radiotherapy and chemotherapy. In the present review paper, based on literature data, the physiological and pathophysiological roles of TRDMT1 in different biological systems are described with the emphasis on human normal and cancer cells. Potential TRDMT1 substrates, inhibitors and regulatory mechanisms of catalytic activity and cellular localization are also presented and evaluated. TRDMT1 as a novel promising target in anticancer therapy is proposed and discussed.
Topics: Humans; DNA (Cytosine-5-)-Methyltransferases; Methyltransferases; RNA, Transfer; Neoplasms; Methylation; DNA
PubMed: 37625528
DOI: 10.1016/j.bbcan.2023.188964 -
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 -
Plant Signaling & Behavior Dec 2023Methyltransferase (MTase) enzymes catalyze the addition of a methyl group to a variety of biological substrates. MTase-like (METTL) proteins are Class I MTases whose...
Methyltransferase (MTase) enzymes catalyze the addition of a methyl group to a variety of biological substrates. MTase-like (METTL) proteins are Class I MTases whose enzymatic activities contribute to the epigenetic and epitranscriptomic regulation of multiple cellular processes. N-adenosine methylation (mA) is a common chemical modification of eukaryotic and viral RNA whose abundance is jointly regulated by MTases and METTLs, demethylases, and mA binding proteins. mA affects various cellular processes including RNA degradation, post-transcriptional processing, and antiviral immunity. Here, we used and plum pox virus (PPV), an RNA virus of the family, to investigated the roles of MTases in plant-virus interaction. RNA sequencing analysis identified MTase transcripts that are differentially expressed during PPV infection; among these, accumulation of a METTL gene was significantly downregulated. Two METTL transcripts (NbMETTL1 and NbMETTL2) were cloned and further characterized. Sequence and structural analyses of the two encoded proteins identified a conserved S-adenosyl methionine (SAM) binding domain, showing they are SAM-dependent MTases phylogenetically related to human METTL16 and FIONA1. Overexpression of NbMETTL1 and NbMETTL2 caused a decrease of PPV accumulation. In sum, our results indicate that METTL homologues participate in plant antiviral responses.
Topics: Humans; Methyltransferases; Nicotiana; Methylation; S-Adenosylmethionine; Antiviral Agents
PubMed: 37210738
DOI: 10.1080/15592324.2023.2214760 -
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 -
RNA Biology Mar 2017Cellular RNAs with diverse chemical modifications have been observed, and N-methyladenosine (mA) is one of the most abundant internal modifications found on mRNA and... (Review)
Review
Cellular RNAs with diverse chemical modifications have been observed, and N-methyladenosine (mA) is one of the most abundant internal modifications found on mRNA and non-coding RNAs, playing a vital role in diverse biologic processes. In humans, mA modification is catalyzed by the METTL3-METTL14 methyltransferase complex, which is regulated by WTAP and another factor. Three groups have recently and independently reported the structure of this complex with or without cofactors. Here, we focus on the detailed mechanism of the mA methyltransferase complex and the properties of each subunit. METTL3 is predominantly catalytic, with a function reminiscent of N-adenine DNA methyltransferase systems, whereas METTL14 appears to be a pseudomethyltransferase that stabilizes METTL3 and contributes to target RNA recognition. The structural and biochemical characterization of the METTL3-METTL14 complex is a major step toward understanding the function of mA modification and developing mA-related therapies.
Topics: Adenosine; Catalysis; Cell Cycle Proteins; Epigenesis, Genetic; Humans; Methylation; Methyltransferases; Nuclear Proteins; RNA; RNA Splicing Factors; Structure-Activity Relationship
PubMed: 28121234
DOI: 10.1080/15476286.2017.1282025 -
Oncogene Mar 2023Alternative splicing (AS) enables differential inclusion of exons from a given transcript, thereby contributing to the transcriptome and proteome diversity. Aberrant AS...
Alternative splicing (AS) enables differential inclusion of exons from a given transcript, thereby contributing to the transcriptome and proteome diversity. Aberrant AS patterns play major roles in the development of different pathologies, including breast cancer. N-methyladenosine (mA), the most abundant internal modification of eukaryotic mRNA, influences tumor progression and metastasis of breast cancer, and it has been recently linked to AS regulation. Here, we identify a specific AS signature associated with breast tumorigenesis in vitro. We characterize for the first time the role of METTL3 in modulating breast cancer-associated AS programs, expanding the role of the mA-methyltransferase in tumorigenesis. Specifically, we find that both mA deposition in splice site boundaries and in splicing and transcription factor transcripts, such as MYC, direct AS switches of specific breast cancer-associated transcripts. Finally, we show that five of the AS events validated in vitro are associated with a poor overall survival rate for patients with breast cancer, suggesting the use of these AS events as a novel potential prognostic biomarker.
Topics: Humans; Female; Alternative Splicing; Breast Neoplasms; Methyltransferases; Transcriptome; Carcinogenesis
PubMed: 36725888
DOI: 10.1038/s41388-023-02602-z -
International Journal of Molecular... Sep 2023N6‑methyladenosine (m6A) RNA methylation is one of the most common post‑transcriptional modification mechanism in eukaryotes. m6A is involved in almost all stages of... (Review)
Review
N6‑methyladenosine (m6A) RNA methylation is one of the most common post‑transcriptional modification mechanism in eukaryotes. m6A is involved in almost all stages of the mRNA life cycle, specifically regulating its stability, splicing, export and translation. Methyltransferase‑like 14 (METTL14) is a particularly important m6A methylation 'writer' that can recognize RNA substrates. METTL14 has been documented to improve the activity and catalytic efficiency of METTL3. However, as individual proteins they can also regulate different biological processes. Malignancies in the digestive system are some of the most common malignancies found in humans, which are typically associated with poor prognoses with limited clinical solutions. METTL14‑mediated methylation has been implicated in both the potentiation and inhibition of digestive system tumor growth, cell invasion and metastasis, in addition to drug resistance. In the present review, the research progress and regulatory mechanisms of METTL14‑mediated methylation in digestive system malignancies were summarized. In addition, future research directions and the potential for its clinical application were examined.
Topics: Humans; Methylation; Digestive System Neoplasms; Gastrointestinal Neoplasms; RNA; Methyltransferases
PubMed: 37539726
DOI: 10.3892/ijmm.2023.5289