Computational insights into the mutagenicity of two tobacco-derived carcinogenic DNA lesions.

Katie A Wilson,Josh L Garden,Natasha T Wetmore,Stacey D Wetmore

doi:10.1093/nar/gky1071

Abstract

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent carcinogen found in all tobacco products that leads to a variety of DNA lesions in cells, including O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G) and O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (PHB-G), which differ by only a single substituent in the bulky moiety. This work uses a multiscale computational approach to shed light on the intrinsic conformational and base-pairing preferences of POB-G and PHB-G, and the corresponding properties in DNA and the polymerase η active site. Our calculations reveal that both lesions form stable pairs with C and T, with the T pairs being the least distorted relative to canonical DNA. This rationalizes the experimentally reported mutational profile for POB-G and validates our computational model. The same approach predicts that PHB-G is more mutagenic than POB-G due to a difference in the bulky moiety hydrogen-bonding pattern, which increases the stability of the PHB-G:T pair. The mutagenicity of PHB-G is likely further increased by stabilization of an intercalated DNA conformation that is associated with deletion mutations. This work thereby uncovers structural explanations for the reported mutagenicity of POB-G, provides the first clues regarding the mutagenicity of PHB-G and complements a growing body of literature highlighting that subtle chemical changes can affect the biological outcomes of DNA adducts.

Highlights

Nitrosamines are a large group of compounds that occur in the human diet, cosmetics, and tobacco, as well as flexible plastics such as balloons, condoms and baby bottle nipples [1,2,3]
Quantum mechanical calculations reveal that both POB-G and PHB-G possess a high degree of inherent conformational flexibility, which may affect the biological processing of the lesions and emphasizes the importance of dynamical structural data for other flexible DNA lesions
When dCTP and dTTP are placed opposite POB-G or PHB-G, the pol ␩ active site is aligned for catalysis and the dNTP forms stable interactions with both lesions

Summary

Introduction

Nitrosamines are a large group of compounds that occur in the human diet, cosmetics, and tobacco, as well as flexible plastics such as balloons, condoms and baby bottle nipples [1,2,3]. NNK is the only tobacco component that has led to lung cancer in every species tested (i.e. mice, rats, hamsters, rabbits, pigs, monkeys and humans) regardless of the route of administration [8,9]. Changes in cigarette design since the 1950s and new routes of tobacco administration have increased human exposure to NNK, and led to an increase in the number of cases of adenocarcinoma (a form of lung cancer) [11,12]. Lung cancer is the most common cancer caused by NNK and is the leading cause of cancer death worldwide in part due to a survival rate of only 18% [13]

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