Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Procainamide, a widely used antiarrythmic, causes DNA hypomethylation in the human T cell line Jurkat, but the mechanism is unknown. We report that procainamide inhibits the DNA methyltransferase catalyzed transfer of methyl groups from S-adenosylmethionine to DNA, but has no effect on other known regulators of DNA methylation. Our results suggest that procainamide could inhibit cellular DNA methylation by inhibiting DNA methyltransferase activity.
 ...
PMID:Procainamide inhibits DNA methyltransferase in a human T cell line. 206 44

DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of autoimmunity, aging and cancer. Evidence for a role in autoimmunity comes from studies demonstrating that inhibiting T lymphocyte DNA methylation causes autoreactivity in vitro and a lupus-like disease in vivo. The autoimmunity is due in part to the heterodimeric beta(2) integrin lymphocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) overexpression, and T lymphocytes from lupus patients hypomethylate the same CD11a promoter sequences, overexpress LFA-1 and demonstrate the same autoreactivity. Procainamide and hydralazine, two drugs that cause a lupus-like disease, also inhibit T cell DNA methylation, increase LFA-1 expression and induce autoreactivity in vitro and autoimmunity in vivo, supporting the association of DNA hypomethylation and autoimmunity. Methylation patterns also change with age in T lymphocytes as well as other tissues, typically with an overall decrease in methylcytosine content, but with increases in some cytosine guanine dinucleotide (CpG) islands. Age-dependent hypomethylation contributes to LFA-1 overexpression with aging, which may play a role in the development of autoimmunity in the elderly and age-dependent methylation of CpG islands in the promoters of tumor suppressor genes is an early event in the development of some cancers. DNA hypomethylation also may contribute to carcinogenesis by promoting overexpression of proto-oncogenes, chromosomal translocations and loss of imprinting. The mechanisms causing altered DNA methylation in autoimmunity, aging and carcinogenesis are incompletely characterized but include exposure to environmental agents and drugs, diet, altered signaling in pathways regulating DNA methyltransferase expression and changes in endogenous regulatory mechanisms. Other mechanisms are likely to be identified as well.
 ...
PMID:Role of DNA methylation in the regulation of cell function: autoimmunity, aging and cancer. 1216

Exposing genetically predisposed individuals to certain environmental agents is believed to cause human lupus. How environmental agents interact with the host to cause lupus is poorly understood. Procainamide and hydralazine are drugs that cause lupus in genetically predisposed individuals. Understanding how these environmental agents cause lupus may indicate mechanisms relevant to the idiopathic disease. Abnormal T cell DNA methylation, a repressive epigenetic DNA modification, is implicated in procainamide and hydralazine induced lupus, as well as idiopathic lupus. Procainamide is a competitive DNA methyltransferase (Dnmt) inhibitor, hydralazine inhibits ERK pathway signaling thereby decreasing Dnmt expression, and in lupus T cells decreased ERK pathway signaling causing a similar Dnmt decrease. T cells treated with procainamide, hydralazine, and other Dnmt and ERK pathway inhibitors cause lupus in mice. Whether the same genetic regulatory elements demethylate in T cells treated with Dnmt inhibitors, ERK pathway inhibitors, and in human lupus is unknown. CD70 (TNFSF7) is a B cell costimulatory molecule overexpressed on CD4(+) lupus T cells as well as procainamide and hydralazine treated T cells, and contributes to excessive B cell stimulation in vitro and in lupus. In this report we identify a genetic element that suppresses CD70 expression when methylated, and which demethylates in lupus and in T cells treated with Dnmt and ERK pathway inhibitors including procainamide and hydralazine. The results support a model in which demethylation of specific genetic elements in T cells, caused by decreasing Dnmt expression or inhibiting its function, contributes to drug-induced and idiopathic lupus through altered gene expression.
 ...
PMID:Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. 1587 18

CpG island hypermethylation occurs in most cases of cancer, typically resulting in the transcriptional silencing of critical cancer genes. Procainamide has been shown to inhibit DNA methyltransferase activity and reactivate silenced gene expression in cancer cells by reversing CpG island hypermethylation. We report here that procainamide specifically inhibits the hemimethylase activity of DNA methyltransferase 1 (DNMT1), the mammalian enzyme thought to be responsible for maintaining DNA methylation patterns during replication. At micromolar concentrations, procainamide was found to be a partial competitive inhibitor of DNMT1, reducing the affinity of the enzyme for its two substrates, hemimethylated DNA and S-adenosyl-l-methionine. By doing so, procainamide significantly decreased the processivity of DNMT1 on hemimethylated DNA. Procainamide was not a potent inhibitor of the de novo methyltransferases DNMT3a and DNMT3b2. As further evidence of the specificity of procainamide for DNMT1, procainamide failed to lower genomic 5-methyl-2'-deoxycytidine levels in HCT116 colorectal cancer cells when DNMT1 was genetically deleted but significantly reduced genomic 5-methyl-2'-deoxycytidine content in parental HCT116 cells and in HCT116 cells where DNMT3b was genetically deleted. Because many reports have strongly linked DNMT1 with epigenetic alterations in carcinogenesis, procainamide may be a useful drug in the prevention of cancer.
 ...
PMID:Procainamide is a specific inhibitor of DNA methyltransferase 1. 1623 Mar 60