The Role of DNA Methylation in the Tumourgenesis - 3850 Words

The Role of DNA Methylation in the Tumourgenesis (Research Paper Sample) Content: The Role of DNA Methylation in the TumourgenesisInsert name (s)Course Instructorà ¢Ã¢â€š ¬s nameCourse CodeDate of SubmissionThe Role of DNA Methylation in the TumourgenesisOverview of DNA MethylationÂDNA methylation is a critically important epigenetic alteration involving the covalent addition of a methyl group to cytosine, guanine or adenine within CpG dinucleotides of the animal cells. According to many experts, DNA methylation plays a very important role in healthy growth and development as it is associated to various processes in living organisms. In addition, DNA methylation is also an essential process required for proper embryonic development and cellular differentiation particularly in higher animals. This is particularly because the biochemical addition of the methyl groups may result in a number of profound effects on the mammalian genome some of which may include transcriptional repression, X chromosome inactivation, carcinogenesis and genomic suppre ssion (Santella, 2011, p.293).Recent studies have revealed that DNA methylation is a crucial player in both genome stability and DNA repair. In normal cells, the epigenetic modification is particularly responsible for ensuring proper regulation of stable gene slicing and gene expression. However, given its critical role in gene expression, errors in DNA methylation have been known to give rise to a diverse number of devastating consequences including abnormalities and diseases such as cancer (Phillips,Â2008, p.116). The correlation between DNA methylation and tumourgenesis is particularly attributed to the silencing of the critical growth regulators like the tumor suppressing genes by DNA methylation due to hypermethylation within the promoter regions. This dissertation critically investigates the potential role of DNA methylation in the tumourgenesis. 1 DNA Methylation MachineryThe DNA methylation machinery primarily consists of DNA methyltransferases (which act as highlighters ), readers of the methylation mark (glasses) as well as erasers. Generally, the machinery particularly works by ensuring that certain genes are turned on at the proper time and turned off when they are not required.The DNA methyltransferases (highlighters) also known as DNA MTases or DNMTs refers to a family of enzymes that are primarily responsible for catalyzing the transfer of methyl group during the DNA methylation process. According to many experts, the enzyme DNA methyltransferases particularly catalyzes the DNA methylation by initiating and speeding up the addition of methyl groups to the 5th carbon position of the cytosine (cytosine-5)Âring within the CpG dinucleotides thereby resulting in 5-methylcytosine.According to Gnyszka, Jastrzebski and Flis (2013, p.2989), there are three DNMTs responsible for the establishment and maintenance of the DNA methylation process namely the DNMT1,ÂDNMT3aÂandÂDNMT3b. DNMT1 is the most abundant enzyme DNA methyltransferase p articularly in the mammalian cells where it is primarily responsible for methylating hemimethylated CpG dinucleotides as well as the maintenance of methyltranferase. On the other hand, DNMT3aÂnormally methylates CpG dinucleotides at a faster rate than DNMT3b but slightly slower than DNMT1.Another key component of the DNA methylation machinery is the methylation mark readers also known as the methyl-CpG-binding proteins. The readers particularly work by specifically binding to the methylated DNA thereby silencing transcription and modulating gene expression. In most cases, the activities of the methyl-CpG-binding proteins (readers) are closely supported by the local chromatin structures which are often primarily responsible for determining the repression or transcription of certain genes. For example, a number of methyl-CpG-binding proteins are widely thought to repress gene expression through their subsequent interactions with the enzymes histone deacetylases. In this regard, th e state of then chromatin structure may be critically important in the regulation of transcription and repression of genes. Finally, the erasers are a part of the DNA methylation machinery which primarily functions by inhibiting methylation initiated suppression thereby redepressing the silenced genes.Fig 1: DNA Methylation Machinery 2 Dynamics of DNA Methylation in Human GenomeThe human genome is widely known to contain two sets of information namely genetic and epigenetic. The epigenetic information is primarily responsible for providing the needed blueprint for the processing and manufacture of all the important proteins required for the survival of micro organisms while the epigenetic information is used to determine where, how and when the genetic information should be used including its transcription and suppression (Esteller, 2011, p.3007). DNA Methylation is one of the major forms of epigenetic information in the human genome that is responsible for ensuring that certain gen es are turned on at the proper time and turned off when they are not required through the covalent addition of a methyl group to cytosine within CpG dinucleotides.Generally, the methylation of DNA in the human genome may potentially affect the binding of proteins to their various cognate DNA sequences thereby resulting in a number of effects on the genome. According to many experts, DNA Methylation normally has a diverse number of profound effects on the human genome some of which usually include epigenetic inheritance, genomic stability, transcriptional repression, X chromosome inactivation, carcinogenesis, suppression and imprinting of parasitic DNA sequences. However, changes in the DNA methylation have in numerous cases been correlated with genetic lesions and genomic instability. 3 Mechanism of DNA Methylation in Gene ExpressionDNA methylation is one of the major epigenetic mechanisms used by the animal cells to control and regulate gene expression. Methylation of DNA is a proc ess where methyl (CH3) group is added to cytosine or guanine/ DNA nucleotides, the cells then uses these epigenetic methods to control/silence gene expression. Gene expression however on the other hand is the process by which information from aÂgeneÂis used in the production of a functionalÂgeneÂproduct for example protein, but in non-protein coding genes such as tiny nuclear RNA, the product after synthesis is a functional RNA (Esteller, 2011, 3005).The mechanism generally entails conversion of the of cytosine bases of the DNA to 5-methylcytosine through the addition of methyl groups to the 5th carbon position of the cytosine (cytosine-5)Âring in the CpG dinucleotides. In this regard, the DNA methylation machinery particularly works by ensuring that certain genes are turned on at the proper time and turned off when they are not required. This is widely attributed to the fact that the epigenetic information is primarily responsible for providing the needed bluepr int for the processing and manufacture of all the important proteins required for the survival of micro organisms while the epigenetic information is used to determine where, how and when the genetic information should be used including its transcription and suppression.According to Knudson (2001, p.158), the methylation of DNA in the human genome may potentially affect the binding of proteins to their various cognate DNA sequences thereby resulting in a number of effects on the genome. As earlier been noted, the entire process is normally catalyzed by DNA methyltransferase (DNMT) enzymes. A number of recent researches have particularly revealed that DNA methylation primarily takes place at the cytosine bottom ofÂeukaryoticÂDNA, which are then converted to 5-methylcytosine by the DNA Methyltransferase enzymes. The altered cytosine residues are then put in place on a DNA sequence and eventually replicated thereby resulting in changes in the gene expression.Although the exact mechanism of methylation in the gene expression is not fully understood, it is widely believed that Methylation plays a critically important role in repressing gene expression and one way is by blocking the promoters. For example, According to Phillips (2008), there exist many ways in which gene expression can be controlled in cells some of which includes numerous cellular processes such as inactivation of the X-chromosome, preventing chromosome stability, embryonic development and genomic imprinting but regardless of all these, methylation of DNA is the most commonly preferred and used method by cells to put genes in an "off" position because these other methods are linked to many errors that leads to devastating consequences such as human diseases.In addition, for better embryonic development and cell differentiation, proper DNA methylation is highly recommended. During the process of cell cycle, the patterns of this histone methylation may change rapidly though methylation of DNA is believed to be quite stable in somatic cells. On the other hand, the aberrant methylation process which is the most common molecular laceration of the cancer cells and it is a big factor to be considered as it causes most human diseases. For gene transcription to take place, the gene promoter must be readily accessible to transcription factors and other regulatory units e.g. the enhancers. 4 DNA Methylation Changes in CancerTurmorgenesis and the development of cancer normally occur as a result of both genetic and epigenetic alterations. According to the widely accepted hypothesis proposed by Knudson (2001, .156) known as the "Two genetic hitsà ¢Ã¢â€š ¬Ã‚ , the carcinogenesis involves two hits namely the first (active) hit inform of genetic alterations such as mutations in a critical gene and the second hit in the form of silence epigenetic alterations resulting in the inactivation or ...