Methylation of tRNAAsp by the DNA Methyltransferase Homolog Dnmt2

Science ◽  
2006 ◽  
Vol 311 (5759) ◽  
pp. 395-398 ◽  
Author(s):  
Mary Grace Goll ◽  
Finn Kirpekar ◽  
Keith A. Maggert ◽  
Jeffrey A. Yoder ◽  
Chih-Lin Hsieh ◽  
...  
Keyword(s):  
Small Rna ◽  
Dna Methyltransferase ◽  
Dna Methyltransferases ◽  
Transfer Rna ◽  
Modified Nucleosides ◽  
Anticodon Loop ◽  
Sequence Recognition ◽  
Eukaryotic Dna ◽  
Biochemical Approach

The sequence and the structure of DNA methyltransferase-2 (Dnmt2) bear close affinities to authentic DNA cytosine methyltransferases. A combined genetic and biochemical approach revealed that human DNMT2 did not methylate DNA but instead methylated a small RNA; mass spectrometry showed that this RNA is aspartic acid transfer RNA (tRNAAsp) and that DNMT2 specifically methylated cytosine 38 in the anticodon loop. The function of DNMT2 is highly conserved, and human DNMT2 protein restored methylation in vitro to tRNAAsp from Dnmt2-deficient strains of mouse, Arabidopsis thaliana, and Drosophila melanogaster in a manner that was dependent on preexisting patterns of modified nucleosides. Indirect sequence recognition is also a feature of eukaryotic DNA methyltransferases, which may have arisen from a Dnmt2-like RNA methyltransferase.

Quantitative aspects of metal ion binding to certain transfer RNA anticodon loop modified nucleosides

1984 ◽  
Vol 802 (2) ◽  
pp. 352-361 ◽  
Author(s):  
M SCHWEIZER ◽  
N DE ◽  
M PULSIPHER ◽  
M BROWN ◽  
P REDDY ◽  
...  
Keyword(s):  
Metal Ion ◽  
Transfer Rna ◽  
Modified Nucleosides ◽  
Ion Binding ◽  
Anticodon Loop ◽  
Metal Ion Binding

Dynamic changes of global DNA methylation and hypermethylation of cell adhesion-related genes in rat kidneys in response to ochratoxin A

2015 ◽  
Vol 8 (4) ◽  
pp. 465-476 ◽  
Author(s):  
X. Li ◽  
J. Gao ◽  
K. Huang ◽  
X. Qi ◽  
Q. Dai ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Adhesion ◽  
Ochratoxin A ◽  
Transcriptional Activation ◽  
Dna Methyltransferase ◽  
Dna Methyltransferases ◽  
Global Dna Methylation ◽  
Specific Cell

Ochratoxin A (OTA), which is found in a variety of food products, is associated with the development of nephrotoxicity and carcinogenicity in rats and has raised public health concerns. A previous study in our laboratory indicated that OTA exposure induced cytotoxicity by decreasing global DNA methylation in vitro. However, the relationship between OTA-induced nephrotoxicity and DNA methylation changes in vivo remains unclear. The object of this study was to investigate whether OTA can change global DNA methylation or alter the expression of several critical tumour-related genes by inducing methylation modifications before carcinogenesis. We focused on the mechanism of action of OTA in regard to DNA methylation, including the expression of DNA methyltransferases and the regulation of specific cell signalling pathways. Dynamic and dose-dependent changes of global DNA methylation were observed during OTA-induced nephrotoxicity and probably associated with the expression of DNA methyltransferase 1. 13-week exposure of OTA caused hypermethylation in the promoters of critical cell adhesion-related genes, E-cadherin and N-cadherin, leading to reduction of the corresponding mRNA expression, accompanied by transcriptional activation of the Wnt and PI3K/AKT pathways. These findings suggested that long-term OTA exposure could disrupt DNA methylation profile, which might be one of the possible mechanisms of OTA-induced nephrotoxicity.

scholarly journals Identification of Novel Bacterial M.SssI DNA Methyltransferase Inhibitors

2012 ◽  
Vol 18 (3) ◽  
pp. 348-355 ◽  
Author(s):  
Marlinda Hupkes ◽  
Rita Azevedo ◽  
Hans Jansen ◽  
Everardus J. van Zoelen ◽  
Koen J. Dechering
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Homology Model ◽  
Binding Mode ◽  
Dna Methyltransferases ◽  
Docking Studies ◽  
Dna Methyltransferase Inhibitors ◽  
Dnmt Inhibitors ◽  
Starting Point

DNA methylation is an important epigenetic regulator of gene expression. Abnormalities in DNA methylation patterns have been associated with various developmental and proliferative diseases, particularly cancer. Targeting DNA methyltransferases (DNMTs) represents a promising strategy for the treatment of such diseases. Current DNMT inhibitors suffer important drawbacks with respect to their efficacy, specificity, and toxicity. In this study, we have set up a robust in vitro bacterial M.SssI DNMT activity assay to systematically screen a collection of 26 240 compounds that were predicted to compete with the S-adenosyl-L-methionine (SAM) substrate of DNMT. This resulted in the identification of a novel set of structurally distinct inhibitors of M.SssI DNMT activity. Although molecular docking studies using an M.SssI homology model suggest that these compounds might compete with SAM binding, mode of activity (MoA) assays are still needed to confirm this hypothesis. Our set of novel M.SssI DNMT inhibitors, once confirmed in an orthogonal DNMT assay, may thus serve as a starting point to identify and characterize suitable lead candidates for further drug optimization.

scholarly journals Murine De Novo Methyltransferase Dnmt3a Demonstrates Strand Asymmetry and Site Preference in the Methylation of DNA In Vitro

2002 ◽  
Vol 22 (3) ◽  
pp. 704-723 ◽  
Author(s):  
Iping G. Lin ◽  
Li Han ◽  
Alexander Taghva ◽  
Laura E. O’Brien ◽  
Chih-Lin Hsieh
Keyword(s):  
Dna Methyltransferase ◽  
De Novo ◽  
Dna Methyltransferases ◽  
Site Preference ◽  
Cpg Sites ◽  
Methylation Of Dna ◽  
Wide Range ◽  
Methylation Patterns

ABSTRACT CpG methylation is involved in a wide range of biological processes in vertebrates as well as in plants and fungi. To date, three enzymes, Dnmt1, Dnmt3a, and Dnmt3b, are known to have DNA methyltransferase activity in mouse and human. It has been proposed that de novo methylation observed in early embryos is predominantly carried out by the Dnmt3a and Dnmt3b methyltransferases, while Dntm1 is believed to be responsible for maintaining the established methylation patterns upon replication. Analysis of the sites methylated in vivo using the bisulfite genomic sequencing method confirms the previous finding that some regions of the plasmid are much more methylated by Dnmt3a than other regions on the same plasmid. However, the preferred targets of the enzyme cannot be determined due to the presence of other methylases, DNA binding proteins, and chromatin structure. To discern the DNA targets of Dnmt3a without these compounding factors, sites methylated by Dnmt3a in vitro were analyzed. These analyses revealed that the two cDNA strands have distinctly different methylation patterns. Dnmt3a prefers CpG sites on a strand in which it is flanked by pyrimidines over CpG sites flanked by purines in vitro. These findings indicate that, unlike Dnmt1, Dnmt3a most likely methylates one strand of DNA without concurrent methylation of the CpG site on the complementary strand. These findings also indicate that Dnmt3a may methylate some CpG sites more frequently than others, depending on the sequence context. Methylation of each DNA strand independently and with possible sequence preference is a novel feature among the known DNA methyltransferases.

scholarly journals Polycomb protein Cbx4 promotes SUMO modification of de novo DNA methyltransferase Dnmt3a

2007 ◽  
Vol 405 (2) ◽  
pp. 369-378 ◽  
Author(s):  
Bing Li ◽  
Jing Zhou ◽  
Peng Liu ◽  
Jialei Hu ◽  
Hong Jin ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
De Novo ◽  
Specific Interaction ◽  
Regulatory Region ◽  
Dna Methyltransferases ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Post Translational Modification ◽  
Sumo Modification

The ‘de novo methyltransferase’ Dnmt3a (DNA methyltransferase 3a) has been shown to mediate transcriptional repression. Post-translational modification of Dnmt3a by SUMOylation affects its ability to transcriptionally repress. However, very little is known about how the SUMOylation process is regulated. In the present study, we identified a PcG (Polycomb group) protein, Cbx4 (chromobox 4), as a specific interaction partner of Dnmt3a. Co-expression of Cbx4 and SUMO-1 (small ubiquitin-related modifier-1) along with Dnmt3a in transfected cells results in enhanced modification of Dnmt3a with SUMO-1. Purified Cbx4 also promotes SUMOylation of Dnmt3a in vitro. The modification occurs in the N-terminal regulatory region, including the PWWP (Pro-Trp-Trp-Pro) domain. Our results suggest that Cbx4 functions as a SUMO E3 ligase for Dnmt3a and it might be involved in the functional regulation of DNA methyltransferases by promoting their SUMO modification.

scholarly journals An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Alexandre Chan ◽  
Angie Yeo ◽  
Maung Shwe ◽  
Chia Jie Tan ◽  
Koon Mian Foo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cognitive Impairment ◽  
Cognitive Function ◽  
Cancer Patients ◽  
Dna Methyltransferase ◽  
Dna Methyltransferases ◽  
Breast Cancer Patients ◽  
Prospective Longitudinal Study ◽  
Cognitive Domains ◽  
Prospective Longitudinal

Abstract Strong evidence suggests that genetic variations in DNA methyltransferases (DNMTs) may alter the downstream expression and DNA methylation patterns of neuronal genes and influence cognition. This study investigates the association between a DNMT1 polymorphism, rs2162560, and chemotherapy-associated cognitive impairment (CACI) in a cohort of breast cancer patients. This is a prospective, longitudinal cohort study. From 2011 to 2017, 351 early-stage breast cancer patients receiving chemotherapy were assessed at baseline, the midpoint, and the end of chemotherapy. DNA was extracted from whole blood, and genotyping was performed using Sanger sequencing. Patients’ self-perceived cognitive function and cognitive performance were assessed at three different time points using FACT-Cog (v.3) and a neuropsychological battery, respectively. The association between DNMT1 rs2162560 and cognitive function was evaluated using logistic regression analyses. Overall, 33.3% of the patients reported impairment relative to baseline in one or more cognitive domains. Cognitive impairment was observed in various objective cognitive domains, with incidences ranging from 7.2% to 36.9%. The DNMT1 rs2162560 A allele was observed in 21.8% of patients and this was associated with lower odds of self-reported cognitive decline in the concentration (OR = 0.45, 95% CI: 0.25–0.82, P = 0.01) and functional interference (OR = 0.48, 95% CI: 0.24–0.95, P = 0.03) domains. No significant association was observed between DNMT1 rs2162560 and objective cognitive impairment. This is the first study to show a significant association between the DNMT1 rs2162560 polymorphism and CACI. Our data suggest that epigenetic processes could contribute to CACI, and further studies are needed to validate these findings.

scholarly journals Expanding the Structural Diversity of DNA Methyltransferase Inhibitors

2020 ◽  
Vol 14 (1) ◽  
pp. 17
Author(s):  
K. Eurídice Juárez-Mercado ◽  
Fernando D. Prieto-Martínez ◽  
Norberto Sánchez-Cruz ◽  
Andrea Peña-Castillo ◽  
Diego Prada-Gracia ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Dna Methyltransferase ◽  
Structural Diversity ◽  
Dna Methyltransferases ◽  
Dna Methyltransferase Inhibitors ◽  
Epigenetic Drug ◽  
Ic50 Values ◽  
Dietary Component ◽  
Approved Drugs ◽  
Epigenetic Processes

Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed extended connectivity interaction features approach, led to an excellent agreement between the experimental IC50 values and docking scores.

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