The exocyclic cytosine adduct 3,N4-ethenocytosine is highly mutagenic in mammalian cells. We describe the impact of this adduct on DNA duplex stability. The adduct does not disrupt the overall B-form DNA structure; however, structural accommodation of the adduct is necessary at the lesion site. Despite the relatively small structural perturbation imparted by the adduct, there is a large adduct-induced destabilization of the DNA duplex. This destabilization is observed to be independent of the cross-strand partner base and neighbouring base pairs. The thermodynamic origins of the destabilization are, however, strongly dependent on the cross-strand partner base and neighbouring base pairs. Comparisons are made between the impact of the 3,N4-ethenocytosine adduct and other lesions on DNA thermodynamics. The lesions are similar in that all result in destabilization of the DNA duplex. The magnitudes and the thermodynamic origins of that destabilization vary widely, the 3,N4-ethenocytosine adduct being dramatically more destabilizing than other lesions. The impact of damaged sites on the stability of the DNA helix suggests that energetic differences between damaged and normal DNA may contribute to the recognition of damage by the cellular DNA repair machinery.
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