Topic
Methyltransferase
About: Methyltransferase is a research topic. Over the lifetime, 6294 publications have been published within this topic receiving 314874 citations. The topic is also known as: methyltransferases.
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TL;DR: It is demonstrated that two recently identified DNA methyltransferases, DnMT3a and Dnmt3b, are essential for de novo methylation and for mouse development and play important roles in normal development and disease.
5,708 citations
TL;DR: Great potential lies in the development of ‘epigenetic therapies’ — several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.
Abstract: Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. Great potential lies in the development of ‘epigenetic therapies’ — several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.
3,051 citations
TL;DR: Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents and an independent and stronger prognostic factor than age, stage, tumor grade, or performance status.
Abstract: Background The DNA-repair enzyme O 6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of the promoter silences the gene in cancer, and the cells no longer produce MGMT. We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents. Methods We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay. The gliomas were obtained from patients who had been treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, or BCNU). The molecular data were correlated with the clinical outcome. Results The MGMT promoter was methylated in gliomas from 19 of 47 patients (40 percent). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status. Con...
2,109 citations
TL;DR: The biological significance of 5-methylcytosine was in doubt for many years, but is no longer, and it has become clear that programmed changes in methylation patterns are less important in the regulation of mammalian development than was previously believed.
Abstract: The biological significance of 5-methylcytosine was in doubt for many years, but is no longer. Through targeted mutagenesis in mice it has been learnt that every protein shown by biochemical tests to be involved in the establishment, maintenance or interpretation of genomic methylation patterns is encoded by an essential gene. A human genetic disorder (ICF syndrome) has recently been shown to be caused by mutations in the DNA methyltransferase 3B (DNMT3B) gene. A second human disorder (Rett syndrome) has been found to result from mutations in the MECP2 gene, which encodes a protein that binds to methylated DNA. Global genome demethylation caused by targeted mutations in the DNA methyltransferase-1 (Dnmt1) gene has shown that cytosine methylation plays essential roles in X-inactivation, genomic imprinting and genome stabilization. The majority of genomic 5-methylcytosine is now known to enforce the transcriptional silence of the enormous burden of transposons and retroviruses that have accumulated in the mammalian genome. It has also become clear that programmed changes in methylation patterns are less important in the regulation of mammalian development than was previously believed. Although a number of outstanding questions have yet to be answered (one of these questions involves the nature of the cues that designate sites for methylation at particular stages of gametogenesis and early development), studies of DNA methyltransferases are likely to provide further insights into the biological functions of genomic methylation patterns.
2,022 citations
TL;DR: There are multiple families of DNA (cytosine-5) methyltransferases in eukaryotes, and each family appears to be controlled by different regulatory inputs.
Abstract: Ke yW ords 5-methylcytosine, DNA methyltransferase, transposons, genomic imprinting ■ Abstract Large-genome eukaryotes use heritable cytosine methylation to silence promoters, especially those associated with transposons and imprinted genes. Cytosine methylation does not reinforce or replace ancestral gene regulation pathways but instead endows methylated genomes with the ability to repress specific promoters in a manner that is buffered against changes in the internal and external environment. Recent studies have shown that the targeting of de novo methylation depends on multiple inputs; these include the interaction of repeated sequences, local states of histone lysine methylation, small RNAs and components of the RNAi pathway, and divergent and catalytically inert cytosine methyltransferase homologues that have acquired regulatory roles. There are multiple families of DNA (cytosine-5) methyltransferases in eukaryotes, and each family appears to be controlled by different regulatory inputs. Sequence-specific DNA- binding proteins, which regulate most aspects of gene expression, do not appear to be involved in the establishment or maintenance of genomic methylation patterns.
2,020 citations