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In the development and progression of cancer epigenetic events play various essential roles. Loss or inactivation of negative regulators as a result of mutations or deletions related to tumor suppressor genes makes mutation taking place in oncogenes in most cases to gain function. However, DNA mythilation can also lead to the loss of function as a result of epigenetic alteration. Epigenetics can be referred to as heritable alteration in the expression of genes that do not cause nucleotide sequence alteration of genes (Silverman, 2001). Genes are inactivated and silenced when DNA is mythilated and transcription is also initiated. This process is usually dysregulated in tumor cells. As deletion causes aberrant silencing of normal tumor suppression, epigenetic silencing takes place more often in cancer. There are several types of tumor, in particular malignancies and hematopoietic which comprise of myelodyplastic syndrome (MDSs), in which as a result of Leukemic transformation, hypermethilation takes place (Silverman, 2001).
This paper is focuses on coming up with a comprehensive understanding of the molecular mechanism that are associated with mythilation gene related silencing in normal and tumor cells. It also brings about the understanding of effects of chromatin structure and its functions. Due to reversible alteration of epigenetic, DNA mythilation inhibitors like azacitidine can lead to redepression of silenced tumors and help them in gaining their normal functions. Silverman, (2001) asserts that for patient suffering from leukemia and other related conditions, methylation inhibitors can be used as treatment measures to such patients. This paper also provides a summary of molecular biology underlying DNA methylation, discusses its effects on the structure of the chromatin, changes in DNA mythilation in cancer, and the therapeutic measures for treating DNA mythilation inhibitors in order to reactivate inappropriately silenced gene in cancer (Silverman, 2001).
DNA methylation takes place through covalent accumulation of a methyl collection at the 5' carbon of the cytosine ring, which as a result leads to 5-methylcytosine. Such a group of methyl project into the main groove of DNA which efficiently hampers transcription. 5-methylcytosine is found in almost 4% of genomic DNA that is primarily at cytosine-guanosine dinucleotides (GpGs) which evident in mammalian DNA (Jones, 2000). Such CpGs take place at lower than expected frequencies all over the body of human genome but are found frequently in small stretches of DNA namely CpG islands (Silverman, 2001). These islands are typically evident in or close the promoter regions of genes, where transcription occurs. Contrary to the normal circumstances, the amount of genomic DNA where a lot of CpG sites are heavily methylated, CpG islands that are secrated in gemiline tissues act as promoters of normal somatic cells which do not undergo the process of methylation and thus enables expression to take place (Silverman, 2001).
DNA methylation inhibitors
DNA methyltransferase inhibitors transform gene appearance and encourage auto-reactivit. In nonexpressed regions, DNA mythilation aids in maintaining transcriptional silence. For instance, pericentromeric heterochromatin that appears condensed and transcriptionally inactive is usually heavily mythilated. the process of Hypermethylation ensures that DNA is lately replicated or transcriptionally quiescent and suppress the potentially hazardous viral sequence or transposome that may have generated from integrated into such sites that possess sequences that are highly repetitive (Santini, 2001). By contrast such sites are basically unmethylated in promoter region of euchromatin, regardless of the transcription state of the gene. However, the exception of such a rule is evident in mammalian cell whereby the regions are methylated in order to foster transcriptional inactivation. CpG islands situated in promoters of gene that are close to inactivated X chromosome in girls are then methylated just like some of the imprinted genes situated or imprinted where paternal allele are expressed (Jones, 2000).
An epigenetic effect of such a hypermethylation is capable of inducing inevitable alteration in the process of gene expression. The process of methylating DNA repair genes such as MLHI and MGMT which contribute to inactivation, which further cause microsatellite and an increased frequency of mutation. Spontaneous deamination is caused by mythilation which as a result enhances DNA binding of carcinogens. It also increases the absorption of ultraviolet by DNA, all of which can be used in helping to increase the mutation rate as well as subsequent gene inactivation (Jones, 2000).
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Enzymes that catalyse the process of adding a methyl group to residue of cytosine in DNA is referred to as DNMTs and those that are found in mammalian cell include the following: DNMT1, DNMT3a, and DNMT3b. for example, in the development of a mouse, DNMT1 is the one that is responsible for the patterns maintenance of the already made DNA methylation whereby new DNA methylation patterns are established through DNMTs 3a and 3b that mediate the establishment (Jones, 2000).
Regulation of DNA Methylation
According to Jones, (2000) in both normal and tumor cells, methylation of DNA are usually controlled at distinguished levels. Through employing a family of enzymes, the addition of methyl groups is usually done through DNA methyltransferases (DNMTs). The structure of chromatin in the vicinity of gene promoters generally influences the transcriptional activity as well as DNA methylation (Jones, 2000). These are therefore regulated through several varied factors such as spacing of nucleosome accompanied by histon acetylaces that in the latter influences te access to transcriptional factors.
Histone Deacetilation in hibitors
Provided that HDSCs are integral in the process of maintaining transcriptional silence, they might as well cause the increase in gene expression when hypermethylation is not present. Just like the variety of HDAC inhibitors have been indicated to have inhibited histone deacentylation of tumor cells in human beings contributing to acetylated histone protein. In treatment using HDAC inhibitors that lead to growth in leukemic cells the drug holds promise for cancer therapy. HDAC inhibitors go through clinical evaluation for therapeutic measures hematopoietic malignancies which include the natural inhibitos such as HDAC like, trichostatin, hydroxamicacid derivatives (Luebbert, 2000).
It is important to note that mythylation has traces of dominance in relation to histone deacetylation in order to deter transcription from occurring. Treatment with decitabine is then followed by HDAC inhibitors to produce synergistic effects for transcriptionally silenced genes (Jones, 2000). A wide-ranging acquaintance concerning the role of HDACs in tumorigenesis, as well as the roles played by can always be achieved. Even though, various theories have not been comprehended in relation to histone deacetilation in inhibitos, the study encourages that clinical approachs be followed (Luebbert, 2000).
The recognition of the biological significance of DNA mythilation in regulating expression of genes in cancer is generally increasing. It is thus evident that such epigenetic changes discussed above contribute to the alteration of chromatin structure and in the long run regulates transcription, X chromosome inactivation, expression of imprinted genes, and finally the inactivation of tumor suppressor genes (Luebbert, 2000). It is also vital to carry out further studies on how to characterize better the interaction of DNA methylation and histone deacetylation pathways. Furthermore, therapeutic measures with inhibitors of DNA methylation and histone deacetylation being capable to reactivate epigenetically silenced genes which finally can restore normal gene function (Luebbert, 2000). In cancer cells this kind of expression can lead to expression of tumor suppressor genes and reducing apoptosis and growth arrest. It is important to note that HDAC inhibitors may also provide room for further advancements in therapeutic measures of hematopoietic malignancies as well as solid tumors (Santini, 2001).
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