The Influence of Oxidative Stress, Carcinogens and Cloning on DNA ...

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Introduction
regions can suppress the gene expression <strong>of</strong> the associated gene (34, 39) . This gene silencing
takes place as the methylation within promoter regions is associated with transcriptional repression
<strong>of</strong> the gene (40) <strong>and</strong> behaves as a switch <strong>of</strong>f for the affected gene.
1.2.2 Chromatin structure <strong>and</strong> transcription repression
Both DNA methylation <strong>and</strong> histone modification are the two major mechanisms that regulate
gene expression, thus it is very important to underst<strong>and</strong> how the histone modification affects
the chromatin structure that dictates the gene expression pattern emerging from the human
genome.
<strong>The</strong> unmethylated CG dinucleotides in gene promoter regions are free to act as receptors for
the transcription factors <strong>and</strong> enable the initiation <strong>of</strong> the transcription process. However, methylation
<strong>of</strong> CpGs is catalyzed by several DNA methyltransferases as DNMT1 (DNA (cytosine-5-)-methyltransferase-1),
DNMT3a <strong>and</strong> DNMT3b (41) <strong>and</strong> interferes with the binding <strong>of</strong>
many transcription factors (21, 42) . But, methylated CpGs facilitate the assembly <strong>of</strong> transcription
repressor complexes that include histone deacetylases (HDAC), histone methyl transferases
<strong>and</strong> chromatin remodeling ATPase (43) . Finally, this represents a connection between three
mechanisms CpG methylation, chromatin structure modification <strong>and</strong> gene silencing. Clearly,
DNA methylation is involved with silencing <strong>of</strong> the gene, which is suspected to induce a
higher density <strong>of</strong> the chromatin structure. This modification <strong>of</strong> chromatin limits the accessi-
bility to the promoter sites leading to transcription repression (21, 27, 44) .
This complicated mechanism can be clarified in figure 4. <strong>The</strong> methylated CpG sites <strong>of</strong>fer
binding points for m-CpG binding proteins involved in gene repression such as MBD1,
MBD2 (methyl-CpG binding domain-1 <strong>and</strong> 2) <strong>and</strong> MeCP2 (methyl CpG binding protein 2)
(45)
. <strong>The</strong>se proteins in turn <strong>of</strong>fer binding sites to transcriptional co-repressors, which finally
associate with transcription repression mediated factors (histone deacetylase, histone methy-
lases <strong>and</strong> chromatin ATPases) (46) . <strong>The</strong> deacetylation <strong>of</strong> histone (47-49) restricts the access to
promoter regions due to more densely packed nucleosomes <strong>and</strong> more condensed chromatin
structure, leading to repression <strong>of</strong> gene activity <strong>and</strong> stop <strong>of</strong> the transcription (50-52) .