Abstract
Distortions in the DNA sequence, such as damage or mispairs, are specifically recognized and processed by DNA repair enzymes. Many repair proteins and, in particular, glycosylases flip the target base out of the DNA helix into the enzyme’s active site. Our molecular dynamics simulations of DNA with intact and damaged (oxidized) methyl-cytosine show that the probability of being flipped is similar for damaged and intact methyl-cytosine. However, the accessibility of the different 5-methyl groups allows direct discrimination of the oxidized forms. Hydrogen-bonded patterns that vary between methyl-cytosine forms carrying a carbonyl oxygen atom are likely to be detected by the repair enzymes and may thus help target site recognition.
Highlights
The genomic integrity of the cell is constantly threatened by DNA damage, nucleotide changes, deletions or recombinations, or epigenetic modifications, leading to mutations
We have examined the conformation of the DNA double helix carrying the different forms of oxidized and intact methyl cytosine, analyzing the local conformation at the central G:Cox pair
The free energy barrier computed for the flip out of the DNA through the major groove is between 9 and 12 kcal/mol, comparable to the free energy barrier calculated for unmethylated cytosine [14,21,30] and significantly higher than the free energy barrier for the base flip of a mispaired thymine, both computed in a previous study [14]
Summary
The genomic integrity of the cell is constantly threatened by DNA damage, nucleotide changes, deletions or recombinations, or epigenetic modifications, leading to mutations. A complex machinery of interacting DNA processing repair enzymes protects the cell from these distortions. Typical targets of such repair enzymes are abasic sites, damaged or alkylated nucleotides or non-native bases, such as. Glycosylase enzymes recognize mismatches and damage and remove the wrong base
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