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Abstract Objective DNA methyltransferases (DNMTs) take on a relevant role in epigenetic control of cancer proliferation and cell survival. However, the molecular mechanisms underlying the establishment and maintenance of DNA methylation in human cancer remain to be fully elucidated. This study was to investigate that how DNMT1 affected the biological characteristics of colorectal cancer (CRC) cells via modulating methylation of microRNA (miR)‐152‐3p and thymosin β 10 (TMSB10) expression. Methods DNMT1, miR‐152‐3p, and TMSB10 expression, and the methylation of miR‐152‐3p in CRC tissues and cells were detected. SW‐480 and HCT‐116 CRC cells were transfected with DNMT1 or miR‐152‐3p‐related sequences or plasmids to explore their characters in biological functions of CRC cells. The binding relationship between DNMT1 and miR‐152‐3p and the targeting relationship between miR‐152‐3p and TMSB10 were analyzed. The tumor growth was also detected in vivo. Results Upregulated DNMT1, TMSB10, reduced miR‐152‐3p, and methylated miR‐152‐3p were detected in CRC tissues and cells. Silenced DNMT1 or upregulated miR‐152‐3p reduced TMSB10 expression and suppressed CRC progression and tumor growth. Moreover, elevated DNMT1 could reverse the effect of miR‐152‐3p upregulation on CRC development and tumor growth. DNMT1 maintained methylation of miR‐152‐3p. TMSB10 was the direct target gene of miR‐152‐3p. Conclusion The study highlights that silenced DNMT1 results in non‐methylated miR‐152‐3p to depress TMSB10 expression, thereby inhibiting CRC development, which provides a new approach for CRC therapy.Keywords:
DNMT1
DNA methyltransferase
The DNA methyltransferases (DNMTs) found in mammals include DNMT1, DNMT3A, and DNMT3B and are attractive targets in cancer chemotherapy. DNMT1 was the first among the DNMTs to be characterized, and it is responsible for maintaining DNA methylation patterns. A number of DNMT inhibitors have been reported, but most of them are nucleoside analogs that can lead to toxic side effects and lack specificity. By combining docking-based virtual screening with biochemical analyses, we identified a novel compound, DC_05. DC_05 is a non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity toward other AdoMet-dependent protein methyltransferases. Through a process of similarity-based analog searching, compounds DC_501 and DC_517 were found to be more potent than DC_05. These three potent compounds significantly inhibited cancer cell proliferation. The structure-activity relationship (SAR) and binding modes of these inhibitors were also analyzed to assist in the future development of more potent and more specific DNMT1 inhibitors.
DNMT1
DNA methyltransferase
Docking (animal)
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DNMT1
DNA methyltransferase
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DNMT1
DNA methyltransferase
Tetrazole
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Dnmt3a is a de novo DNA methyltransferase that modifies unmethylated DNA. In contrast Dnmt1 shows high preference for hemimethylated DNA. However, Dnmt1 can be activated for the methylation of unmodified DNA. We show here that the Dnmt3a and Dnmt1 DNA methyltransferases functionally cooperate in de novo methylation of DNA, because a fivefold stimulation of methylation activity is observed if both enzymes are present. Stimulation is observed if Dnmt3a is used before Dnmt1, but not if incubation with Dnmt1 precedes Dnmt3a, demonstrating that methylation of the DNA by Dnmt3a stimulates Dnmt1 and that no physical interaction of Dnmt1 and Dnmt3a is required. If Dnmt1 and Dnmt3a were incubated together a slightly increased stimulation is observed that could be due to a direct interaction of these enzymes. In addition, we show that Dnmt1 is stimulated for methylation of unmodified DNA if the DNA already carries some methyl groups. We conclude that after initiation of de novo methylation of DNA by Dnmt3a, Dnmt1 becomes activated by the pre-existing methyl groups and further methylates the DNA. Our data suggest that Dnmt1 also has a role in de novo methylation of DNA. This model agrees with the biochemical properties of these enzymes and provides a mechanistic basis for the functional cooperation of different DNA MTases in de novo methylation of DNA that has also been observed in vivo.
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DNA methyltransferase
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Abstract Background/Objectives It seems that global DNA hypomethylation in CD4+T cells is linked to the pathogenesis of systemic lupus erythematosus ( SLE ). However, the underlying mechanism by which SLE patients show hypomethylated DNA remains unclear. This study explored the relationship between DNA methylation patterns and expression levels of DNA methyltransferases ( DNMT1) and MBD2 in CD4+T cells of SLE patients. Methods CD4+T cells were obtained from 30 patients with SLE and 18 normal controls. The global DNA methylation levels in CD4+T cells were evaluated by the Methyflash DNA methylation quantification kit. The mRNA levels of DNMT1 and MBD2 were quantified by quantitative real‐time polymerase chain reaction. Results SLE patients had significantly lower global DNA methylation levels than controls, and the global DNA methylation was inversely correlated with the SLE disease activity index ( SLEDAI ). The mRNA levels of DNMT1 in SLE patients were significantly lower than that of controls and there was no correlation between DNMT1 mRNA levels and SLEDAI but there was a positive correlation between DNMT1 mRNA levels and global DNA methylation. The mRNA levels of MBD2 in SLE patients were significantly higher than in controls, and there was positive correlation between MBD2 mRNA levels and SLEDAI and an inverse correlation between MBD2 mRNA levels and global DNA methylation. Conclusions Global DNA hypomethylation may play a pivotal role in the pathogenesis of SLE . Abnormal expression levels of DNMT1 and MBD2 mRNA may be important causes of the global hypomethylation observed in CD4+T cells in SLE .
DNMT1
DNA methyltransferase
Pathogenesis
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HCCS
DNMT1
DNA methyltransferase
DNMT3B
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Abstract Methyltransferase inhibitors : Short double‐stranded oligonucleotides that have a hemimethylated target sequence and 5‐fluoro‐2′‐deoxycytidine as a suicide inhibitor as well as their phosphorothioated analogues were tested for their ability to inhibit the bacterial methyltransferase M.HhaI and the human Dnmt1 in vitro. magnified image The cytidine analogue 5‐fluoro‐2′‐deoxycytidine (dC F ) is a mechanism‐based inhibitor of DNA methyltransferases. We report the synthesis of short 18‐mer dsDNA oligomers containing a triple‐hemimethylated CpG motive as a recognition sequence for the human methyltransferase Dnmt1. The DNA strands carry within these CpG islands dC F building blocks that function as mechanism‐based inhibitors of the analyzed methyltransferases. In addition, we replaced the phosphodiester backbones at defined positions by phosphorothioates. These hypermodified DNA strands were investigated as inhibitors of the DNA methyltransferases M.HhaI and Dnmt1 in vitro. We could show that both methylases behave substantially differently in respect to the amount of DNA backbone modification.
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DNA methyltransferase
CpG site
Phosphodiester bond
Cytidine
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5-Methylcytosine residues in the DNA (DNA methylation) are formed from the transfer of the methyl group from S-adenosylmethionine to the C-5 position of cytosine by the DNA-(cytosine-5) methyltransferases (DNMTs). Although regional hypermethylation and global hypomethylation of the genome are commonly observed in neoplastic cells, how these aberrant methylation patterns occur remains unestablished. We report here that sulfonate-derived methylating agents, unlike N-methylnitrosourea or iodomethane, are potent in depleting DNMT1 proteins in human cells, in addition to their DNA-damaging properties. Their effects on cellular DNMT1 are time and dosage dependent but independent of cell type. Unlike gamma-irradiation, these agents apparently do not activate the p53/p21(WAF1) DNA damage response pathway to deplete the DNMT1 proteins because cells with wild-type, mutated, or inactivated p53 behave similarly. However, cell cycle analysis and protease assay studies strongly suggest that methylmethanesulfonate may activate a cellular protease to degrade DNMT1. These results explain why reported observations on the effect of alkylating agents on DNMT1 activities in human cells vary significantly and provide a crucial link to understand the mechanism behind genomic hypomethylation.
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DNA methyltransferase
Cytosine
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DNMT1
DNA methyltransferase
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这份报纸在维护 methyltransferase (DNMT1 ) 和 de novo methyltransferases 的表示模式调查了年龄相关的变化(DNMT3a， 3b， 3L ) 并且在 in-vivo 的染色体建筑学成熟用二光子的扫描激光的显微镜的老鼠卵母细胞。我们的结果显示出那(1 ) DNMT1 和 DNMT3a， 3b，在 pubertal 老鼠的卵母细胞的 3L 位于卵母细胞细胞质的外皮的区域。在年龄组， DNMT1 也位于外皮的区域。然而， DNMT3a， 3b， 3L 在卵母细胞细胞质有相对更宽的分布并且出现在染色体附近。pubertal 和年龄组之间的这些差别建议老化可能影响 DNA methylation；(2 ) DNMT1 的表示，和 DNMT3a，在年龄组的 3b 与 pubertal 组相比显著地增加了，当时， DNMT3L 的表示减少了。这些结果可能被赔偿机制在 DNMT 之中解释，它可能对老化不可渗透；(3 ) 老化在分发和染色体的三维的形态学引起了增加的错误，包括增加的全部的体积和表面区域，到围住染色体(H/D ) 的圆形的柱体的直径的高度的高比率。我们的工作在卵母细胞质量为年龄相关的衰落的研究提供了词法信息。
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DNA methyltransferase
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