Explain the consequences of methylation of CpG dinucleotides in DNA. Focus on th

Question

Explain the consequences of methylation of CpG dinucleotides in DNA. Focus on the following two scenarios in your description:

1.Transition mutations in DNA (that is: C-G T-A).

2. Epigenetic gene silencing (that is: how the CpG methylation in DNA contributes to reduced production of mRNA from a gene).

Underline the following terms in your answer: Deamination, DNA repair, promoter, and chromatin remodeling proteins. Make sure that your answer is cohesive, and that both scenarios are clearly explained. Include1 figure. You are required to illustrate one DNA replication cycle without mismatch repair after the deamination of a methylated cytosine.

Explanation / Answer

The increased mutability of 5-methylcytosine versus cytosine is thought to be influenced by three factors: differential repair efficiency, rate of spontaneous deamination, and rate of cell division. Deamination of cytosine forms uracil, which is readily recognized and repaired by the highly abundant and efficient uracil DNA glycosylase (UDG). However, deamination of 5-methylcytosine forms thymine, a naturally occurring DNA base which is significantly more difficult to detect and repair via the thymine DNA glycosylase (TDG). The end result is an increased CT transition rate at methylated CpG sites. Aberrations in the repair pathways themselves do not seem to be common in human tumors. The second factor, the rate of spontaneous deamination, appears to be relatively constant and is more than sufficient to account for all mutations observed in double-stranded DNA. The third factor influencing the enhanced mutability of 5-methylcytosine versus cytosine is the rate of cell division. In a model bacterial system, 5-methylcytosine was as stable as cytosine when the cells were not dividing. It has in fact been noted that CpG mutations are more common in human cancers where cell division is stimulated by hormones, or in damaged tissues undergoing repair.

CpG sites frequently act as mutational hotspots in the p53 gene. The p53 mutation spectrum for a given tumor type varies, however, and while transition mutations resulting from spontaneous deamination at CpG sites are frequent in colon carcinomas and other internal cancers, GT transversion mutations predominate in lung cancer, and transition mutations at dipyrimidine sequences predominate in skin cancer, reflecting the specificity of the causative exogenous carcinogen

The majority of mutations observed in skin cancer are CT transitions or CCTT mutations at dipyrimidine sequences resulting from UV-light-induced cyclobutane pyrimidine dimer formation

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