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. Include 1 figure. You are required to illustrate one DNA replication cycle without mismatch repair after the deamination of a methylated cytosine.

Explanation / Answer

The term CpG means "cytidine - phosphate - guanidine." In most of the eukaryotes, CpG methylation is done to alter a gene expression. A methyl group is added to 5' C of cytosine ring of the nucleotide. The enzymes that add methyl group are called DNA methyl transferases. unmethylated CpG regions can efficiently bind transcription factors and allow transcription of the gene.

On the other hand, methylated CpG regions, generally located in the promotor regions, prevent the transcription factors from binding the DNA. Methylated DNA binds to proteins called MBD (methyl CpG binding proteins). These proteins interact with histone proteins and lead to tight compaction of the DNA, which makes the DNA region inaccessible to trancription factors.

1. Methylated cytosine is easily prone to spontaneous deamination. This spontaneous deamination of methyl cytosine forms Uracil. Since Uracil is not a component of DNA, the DNA repair enzymes remove it from the DNA strand and replaced with Thymine. During the next round of replication, the strand containing Thymine is base paired to Adenine. Thus, a C - G base pair is mutated to a T - A base pair. This type of replacement of a purine with another purine or a pyrimidine with another pyrimidine is called Transition.

2. Methylated cytosine in DNA attracts and binds methylcytosine binding proteins. These proteins strongly interact with modified histone proteins and lead to chromatin compaction or condensation into transcriptionally inactive conformations (repressive conformations). Chromatin remodelling proteins, which alter the chromatin structure by exposing the wrapped DNA in nucleosomes, cannot act at methylated CpG regions bound tightly to the histones. Thus, they cannot detach histone octamer, cannot effectively open the nucleosome for transcription.

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