Abstract
8-oxoguanine is a major lesion of genomic DNA that results from oxidation of guanine by reactive oxygen species. The repair of this lesion is initiated by 8-oxoguanine glycosylases, which excise the damaged base by "flipping" it outside the DNA double helix. The molecular mechanisms involved in the specific recognition of the damaged base by the enzyme are not yet fully understood. Several models have proposed that, in DNA, the base pair between 8-oxoguanine and cytosine may possess altered dynamic properties that could help the enzyme locate the lesion and could favor the selective extra-helical flipping of the damaged base. To test this proposal, we have characterized the spontaneous opening of the base pair between 8-oxoguanine and cytosine in a DNA double helix using NMR spectroscopy and proton exchange. The results show that the rate of spontaneous opening of 8-oxoguanine and the lifetime of the base in the extra-helical state are the same as those of a canonical guanine-cytosine base pair, in the same base sequence context. This finding suggests that the opening dynamics of 8-oxoguanine, when paired with cytosine in DNA, does not play a significant role in the recognition of the lesion by glycosylases.
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