Maintaining DNA Methylation Research Articles

Targeting DNA methyltransferase in cancer.

DNA methyltransferase is an enzyme responsible for generating and maintaining DNA methylation patterns. DNA methylation patterns control different genome functions, thus they are an important component of the epigenetic information. It has been recently postulated that DNA methyltransferase plays an important role in oncogenesis and that it is a candidate target for anticancer therapy. This commentary discusses the possible mechanisms through which DNA methyltransferase participates in oncogenesis and the rationale for targeting it in cancer.

DNA methylation and retrovirus expression.

The methylation of cytosine in mammalian DNA has proven to be an enigma to scientists since its discovery more than 30 years ago. There are several apparent roles for the methylation of DNA in eukaryotic cells, the exceptions being Drosophila yeast. The absence of DNA methylation in the latter two examples suggests that the fundamental mechanisms of DNA metabolism can exist without modification of cytosine. Probably the most common phenomenon ascribed in DNA methylation is the control of gene activity at the level of transcription (Bird, 1986; Lindsay and Bird, 1988). Methylation of key cytosine moieties is mediated by the mammalian DNA cytosine-5-methyltransferase (MeTase), and is specific for the dinucleotide sequence CpG (Bestor et al., 1988; Doerfler, 1983; Santi et al., 1983; Smith et al., 1991). The CpG sequences are often found localized in clusters and are referred to as “CpG islands” (Bird, 1986). Gene promoters which occupy such islands are susceptible to inactivation, but the process which determines what genes are to be selectively inactivated is currently unknown. A key feature of the regulation of gene activity by hypermethylation of CpG sequences is the epigenetic manner by which the cell strictly maintains DNA methylation patterns. The term “epigenetic” was introduced to permit the addition of another level of information, separate from alteration of the actual gene sequence, to allow the stable inheritance of, in this case, gene activity patterns (Holliday, 1990). The breakdown in the relaying of epigenetic information would result in the disarray of gene expression and ultimately cellular dysfunction.KeywordsHuman Immunodeficiency VirusHuman Immunodeficiency Virus TypeHuman Immune Deficiency VirusHuman Immunodeficiency Virus LatencyTranscriptional BlockThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Growth regulation of mouse DNA methyltransferase gene expression

The steady state level of DNA methyltransferase mRNA is markedly increased as growth-arrested Balb/c 3T3 cells progress into the S phase of the cell cycle. mRNA abundance is reduced to the basal level before termination of DNA synthesis activity. Maintenance DNA methylation activity in nuclear extracts follows a similar pattern with two exceptions. (a) A small peak of DNA methylation activity is detected in early G1 phase. (b) The extinction of DNA methylation activity lags behind the termination of DNA synthesis. Nuclear runon experiments demonstrate that the gene is transcribed in growth-arrested cells, and expression of the gene is post-transcriptionally regulated. We suggest that this mode of regulation of the DNA methyltransferase gene might play an important role in determining and maintaining DNA methylation patterns.

Levels of DNA methylation in diploid and SV40 transformed human fibroblasts

Total 5-methylcytosine (5mC) has been measured in the DNA of cultured human cells by HPLC chromatography. In agreement with other reports, the level of 5mC declines continuously during the serial passaging of diploid fibroblasts, strain MRC-5. On the contrary, fibroblasts infected with SV40, which have acquired most of the properties of transformed cells, maintain a constant level of 5mC, prior to dying out in the crisis period. MRC-5 and Werner's syndrome fibroblasts fully transformed and immortalised by SV40, also maintain a constant level of 5mC. These results indicate that the ability of cells to maintain DNA methylation is a necessary but not a sufficient step for immortalisation.