Dynamic conformational heterogeneities of carcinogen-DNA adducts and their mutagenic relevance

Document Type

Article

Date of Original Version

12-13-2004

Abstract

Arylamines and polycyclic aromatic hydrocarbons (PAHs), which are known as "bulky" carcinogens, have been studied extensively and upon activation in vivo, react with cellular DNA to form DNA-adducts. The available structure data accumulated thus far has revealed that conformational heterogeneity is a common theme among duplex DNA modified with these carcinogens. Several conformationally diverse structures have been elucidated and found to be in equilibrium in certain cases. The dynamics of the heterogeneity appear to be modulated by the nature of the adduct structure and the base sequences neighboring the lesion site. These can be termed as "adduct- and sequence-induced conformational heterogeneities," respectively. Due to the small energy differences, the population levels of these conformers could readily be altered within the active sites of repair or replicate enzymes. Thus, the complex role of "enzyme-induced conformational heterogeneity" must also be taken into consideration for the establishment of a functional structure-mutation relationship. Ultimately, a major challenge in mutation structural biology is to carry out adduct- and site-specific experiments in a conformationally specific manner within biologically relevant environments. Results from such experiments should provide an accurate account of how a single chemically homogenous adduct gives rise to complex multiple mutations, the earliest step in the induction of cancer.

Publication Title, e.g., Journal

Journal of Environmental Science and Health - Part C Environmental Carcinogenesis and Ecotoxicology Reviews

Volume

22

Issue

2

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