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Cells Mar 2022Cardiometabolic diseases (CMDs) are currently the leading cause of death and disability worldwide, and their underlying regulatory mechanisms remain largely unknown.... (Review)
Review
Cardiometabolic diseases (CMDs) are currently the leading cause of death and disability worldwide, and their underlying regulatory mechanisms remain largely unknown. N6-methyladenosine (m6A) methylation, the most common and abundant epigenetic modification of eukaryotic mRNA, is regulated by m6A methyltransferase, demethylase, and the m6A binding protein, which affect the transcription, cleavage, translation, and degradation of target mRNA. m6A methylation plays a vital role in the physiological and pathological processes of CMDs. In this review, we summarize the role played by m6A methylation in CMDs, including obesity, hypertension, pulmonary hypertension, ischemic heart disease, myocardial hypertrophy, heart failure, and atherosclerosis. We also describe mechanisms that potentially involve the participation of m6A methylation, such as those driving calcium homeostasis, circadian rhythm, lipid metabolism, autophagy, macrophage response, and inflammation. m6A methylation and its regulators are expected to be targets for the treatment of CMDs.
Topics: Adenosine; Cardiovascular Diseases; Humans; Methylation; Methyltransferases; RNA, Messenger
PubMed: 35406663
DOI: 10.3390/cells11071101 -
Journal of Translational Medicine May 2022In recent years, 5-methylcytosine (mC) RNA modification has emerged as a key player in regulating RNA metabolism and function through coding as well as non-coding RNAs.... (Review)
Review
In recent years, 5-methylcytosine (mC) RNA modification has emerged as a key player in regulating RNA metabolism and function through coding as well as non-coding RNAs. Accumulating evidence has shown that mC modulates the stability, translation, transcription, nuclear export, and cleavage of RNAs to mediate cell proliferation, differentiation, apoptosis, stress responses, and other biological functions. In humans, mC RNA modification is catalyzed by the NOL1/NOP2/sun (NSUN) family and DNA methyltransferase 2 (DNMT2). These RNA modifiers regulate the expression of multiple oncogenes such as fizzy-related-1, forkhead box protein C2, Grb associated-binding protein 2, and TEA domain transcription factor 1, facilitating the pathogenesis and progression of cancers. Furthermore, the aberrant expression of methyltransferases have been identified in various cancers and used to predict the prognosis of patients. In this review, we present a comprehensive overview of mC RNA methyltransferases. We specifically highlight the potential mechanism of action of mC in cancer. Finally, we discuss the prospect of mC-relative studies.
Topics: 5-Methylcytosine; Humans; Methyltransferases; Neoplasms; RNA; RNA Processing, Post-Transcriptional
PubMed: 35562754
DOI: 10.1186/s12967-022-03427-2 -
Stem Cell Reviews and Reports Jan 2023The methyltransferase-like (METTL) family is a diverse group of methyltransferases that can methylate nucleotides, proteins, and small molecules. Despite this diverse... (Review)
Review
The methyltransferase-like (METTL) family is a diverse group of methyltransferases that can methylate nucleotides, proteins, and small molecules. Despite this diverse array of substrates, they all share a characteristic seven-beta-strand catalytic domain, and recent evidence suggests many also share an important role in stem cell biology. The most well characterized family members METTL3 and METTL14 dimerize to form an N-methyladenosine (mA) RNA methyltransferase with established roles in cancer progression. However, new mouse models indicate that METTL3/METTL14 are also important for embryonic stem cell (ESC) development and postnatal hematopoietic and neural stem cell self-renewal and differentiation. METTL1, METTL5, METTL6, METTL8, and METTL17 also have recently identified roles in ESC pluripotency and differentiation, while METTL11A/11B, METTL4, METTL7A, and METTL22 have been shown to play roles in neural, mesenchymal, bone, and hematopoietic stem cell development, respectively. Additionally, a variety of other METTL family members are translational regulators, a role that could place them as important players in the transition from stem cell quiescence to differentiation. Here we will summarize what is known about the role of METTL proteins in stem cell differentiation and highlight the connection between their growing importance in development and their established roles in oncogenesis.
Topics: Mice; Animals; Methyltransferases; RNA; Embryonic Stem Cells; Cell Differentiation; Biology; Neoplasms
PubMed: 36094754
DOI: 10.1007/s12015-022-10444-7 -
Genes Jan 20195-methylcytosine (m⁵C) is an abundant RNA modification that's presence is reported in a wide variety of RNA species, including cytoplasmic and mitochondrial ribosomal... (Review)
Review
5-methylcytosine (m⁵C) is an abundant RNA modification that's presence is reported in a wide variety of RNA species, including cytoplasmic and mitochondrial ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs), as well as messenger RNAs (mRNAs), enhancer RNAs (eRNAs) and a number of non-coding RNAs. In eukaryotes, C5 methylation of RNA cytosines is catalyzed by enzymes of the NOL1/NOP2/SUN domain (NSUN) family, as well as the DNA methyltransferase homologue DNMT2. In recent years, substrate RNAs and modification target nucleotides for each of these methyltransferases have been identified, and structural and biochemical analyses have provided the first insights into how each of these enzymes achieves target specificity. Functional characterizations of these proteins and the modifications they install have revealed important roles in diverse aspects of both mitochondrial and nuclear gene expression. Importantly, this knowledge has enabled a better understanding of the molecular basis of a number of diseases caused by mutations in the genes encoding m⁵C methyltransferases or changes in the expression level of these enzymes.
Topics: 5-Methylcytosine; Animals; Humans; Methyltransferases; Neurodevelopmental Disorders; RNA Processing, Post-Transcriptional
PubMed: 30704115
DOI: 10.3390/genes10020102 -
Nature Jan 2023Chemical modifications of RNA have key roles in many biological processes. N-methylguanosine (mG) is required for integrity and stability of a large subset of tRNAs. The...
Chemical modifications of RNA have key roles in many biological processes. N-methylguanosine (mG) is required for integrity and stability of a large subset of tRNAs. The methyltransferase 1-WD repeat-containing protein 4 (METTL1-WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types. Mutations in WDR4 cause human developmental phenotypes including microcephaly. How METTL1-WDR4 modifies tRNA substrates and is regulated remains elusive. Here we show, through structural, biochemical and cellular studies of human METTL1-WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the αC region of METTL1 transforms into a helix, which together with the α6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that the predicted disordered N-terminal region of METTL1 is part of the catalytic pocket and essential for methyltransferase activity. Furthermore, we reveal that S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by locally disrupting the catalytic centre. Our results provide a molecular understanding of tRNA substrate recognition and phosphorylation-mediated regulation of METTL1-WDR4, and reveal the presumed disordered N-terminal region of METTL1 as a nexus of methyltransferase activity.
Topics: Humans; Biocatalysis; Catalytic Domain; GTP-Binding Proteins; Methyltransferases; Phosphorylation; RNA Processing, Post-Transcriptional; RNA, Transfer; Substrate Specificity
PubMed: 36599985
DOI: 10.1038/s41586-022-05566-4 -
Molecular Cell Jul 2016N(6)-methyladenosine (m(6)A) is a prevalent, reversible chemical modification of functional RNAs and is important for central events in biology. The core m(6)A writers...
N(6)-methyladenosine (m(6)A) is a prevalent, reversible chemical modification of functional RNAs and is important for central events in biology. The core m(6)A writers are Mettl3 and Mettl14, which both contain methyltransferase domains. How Mettl3 and Mettl14 cooperate to catalyze methylation of adenosines has remained elusive. We present crystal structures of the complex of Mettl3/Mettl14 methyltransferase domains in apo form as well as with bound S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) in the catalytic site. We determine that the heterodimeric complex of methyltransferase domains, combined with CCCH motifs, constitutes the minimally required regions for creating m(6)A modifications in vitro. We also show that Mettl3 is the catalytically active subunit, while Mettl14 plays a structural role critical for substrate recognition. Our model provides a molecular explanation for why certain mutations of Mettl3 and Mettl14 lead to impaired function of the methyltransferase complex.
Topics: Adenosine; Allosteric Regulation; Binding Sites; Catalytic Domain; HEK293 Cells; Humans; Methylation; Methyltransferases; Models, Molecular; Mutation; Protein Binding; Protein Conformation; RNA; S-Adenosylhomocysteine; S-Adenosylmethionine; Structure-Activity Relationship
PubMed: 27373337
DOI: 10.1016/j.molcel.2016.05.041 -
Clinical and Translational Medicine Aug 2023N -methyladenosine (m6A) is of great importance in renal physiology and disease progression, but its function and mechanism in renal fibrosis remain to be...
BACKGROUND
N -methyladenosine (m6A) is of great importance in renal physiology and disease progression, but its function and mechanism in renal fibrosis remain to be comprehensively and extensively explored. Hence, this study will explore the function and potential mechanism of critical regulator-mediated m6A modification during renal fibrosis and thereby explore promising anti-renal fibrosis agents.
METHODS
Renal tissues from humans and mice as well as HK-2 cells were used as research subjects. The profiles of m6A modification and regulators in renal fibrosis were analysed at the protein and RNA levels using Western blotting, quantitative real-time polymerase chain reaction and other methods. Methylation RNA immunoprecipitation sequencing and RNA sequencing coupled with methyltransferase-like 3 (METTL3) conditional knockout were used to explore the function of METTL3 and potential targets. Gene silencing and overexpression combined with RNA immunoprecipitation were performed to investigate the underlying mechanism by which METTL3 regulates the Ena/VASP-like (EVL) m6A modification that promotes renal fibrosis. Molecular docking and virtual screening with in vitro and in vivo experiments were applied to screen promising traditional Chinese medicine (TCM) monomers and explore their mechanism of regulating the METTL3/EVL m6A axis and anti-renal fibrosis.
RESULTS
METTL3 and m6A modifications were hyperactivated in both the tubular region of fibrotic kidneys and HK-2 cells. Upregulated METTL3 enhanced the m6A modification of EVL mRNA to improve its stability and expression in an insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)-dependent manner. Highly expressed EVL binding to Smad7 abrogated the Smad7-induced suppression of transforming growth factor-β (TGF-β1)/Smad3 signal transduction, which conversely facilitated renal fibrosis progression. Molecular docking and virtual screening based on the structure of METTL3 identified a TCM monomer named isoforsythiaside, which inhibited METTL3 activity together with the METTL3/EVL m6A axis to exert anti-renal fibrosis effects.
CONCLUSIONS
Collectively, the overactivated METTL3/EVL m6A axis is a potential target for renal fibrosis therapy, and the pharmacological inhibition of METTL3 activity by isoforsythiaside suggests that it is a promising anti-renal fibrosis agent.
Topics: Animals; Humans; Mice; Fibrosis; Methyltransferases; Molecular Docking Simulation; RNA; RNA, Messenger; RNA-Binding Proteins
PubMed: 37537731
DOI: 10.1002/ctm2.1359 -
Leukemia & Lymphoma Feb 2020DNA methyltransferases (DNMTs) are highly conserved DNA-modifying enzymes that play important roles in epigenetic regulation and they are involved in cell proliferation,... (Review)
Review
DNA methyltransferases (DNMTs) are highly conserved DNA-modifying enzymes that play important roles in epigenetic regulation and they are involved in cell proliferation, differentiation, and apoptosis. In mammalian cells, three active DNMTs have been identified: DNMT1 acts as a maintenance methyltransferase to replicate preexisting methylation patterns, whereas DNMT3A and DNMT3B primarily act as methyltransferases that are responsible for establishing DNA methylation patterns by adding a methyl group to cytosine bases. The expression of is widespread in a variety of hematological cells and it is altered in each type of leukemia, which is associated with its pathogenesis, progression, treatment, and prognosis. Here, we review current information on DNMT3B in leukemia, including its expression, single-nucleotide polymorphisms, mutations, regulation, function, and clinical value for anti-leukemic therapy and prognosis.
Topics: Animals; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Epigenesis, Genetic; Humans; Leukemia; Methyltransferases; Protein Processing, Post-Translational; DNA Methyltransferase 3B
PubMed: 31547729
DOI: 10.1080/10428194.2019.1666377 -
Current Medicinal Chemistry 2023Protein lysine methylation is a significant protein post-translational modification (PTMs) and has a key function in epigenetic regulation. Protein lysine... (Review)
Review
Protein lysine methylation is a significant protein post-translational modification (PTMs) and has a key function in epigenetic regulation. Protein lysine methyltransferase (PKMTs) mainly catalyzes the lysine methylation of various core histones and a few non-histone proteins. It has been observed that aberrant activity of PKMTs has been found in many cancers and other diseases, and some PKMT inhibitors have been discovered and progressed to clinical trials. This field developed rapidly and has aroused great interest. In this paper, we reviewed the biochemical and biological activities of PKMTs and their association with various cancers. Selective small-molecule inhibitors, including their chemical structure, structure-activity relationship, and in vitro/vivo studies, are also described to provide ideas for the discovery of highly potent, selective PKMT inhibitors.
Topics: Humans; Histone-Lysine N-Methyltransferase; Lysine; Epigenesis, Genetic; Histones; Neoplasms; Methyltransferases; Protein Processing, Post-Translational
PubMed: 36043747
DOI: 10.2174/0929867329666220829151257 -
Cell Proliferation Jan 2022N6-Methyladenosine (m6A) is considered the most common and endogenous modification of eukaryotic RNAs. Highly conserved in many species, m6A regulates RNA metabolism,... (Review)
Review
N6-Methyladenosine (m6A) is considered the most common and endogenous modification of eukaryotic RNAs. Highly conserved in many species, m6A regulates RNA metabolism, cell differentiation, cell circadian rhythm, and cell cycle; it also responds to endogenous and exogenous stimuli and is associated with the development of tumors. The m6A methyltransferase complex (MTC) regulates the m6A modification of transcripts and involves two components, methyltransferase-like enzyme 3 (METTL3) and methyltransferase-like enzyme 14 (METTL14), and other auxiliary regulatory distinct components. Though with no catalytic effect, METTL14 serves as an RNA-binding scaffold in MTC, promotes RNA substrate recognition, activates, and escalates the catalytic capability of METTL3, thus accounting for a pivotal member of the complex. It was reported that METTL14 regulates tumor proliferation, metastasis, and self-renewal, and plays a part in tumorigenesis, tumor progression, and other processes. The present work is a review of the role of METTL14 both as a tumor suppressor and a tumor promoter in the oncogenesis and progression of various tumors, as well as the potential molecular mechanisms.
Topics: Adenosine; Animals; Genes, Tumor Suppressor; Humans; Methyltransferases; Neoplasms; Oncogenes; RNA
PubMed: 34904301
DOI: 10.1111/cpr.13168