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Physical binding of the tobacco smoke carcinogen NNK diazonium ion to the human tumor suppressor gene TP53 Exon 5.

ABSTRACT: The tobacco smoke N-nitrosamine, NNK, is an important carcinogen. It has been shown to induce lung, liver, and pancreatic cancer in animals. Its metabolites are associated with lung cancer in tobacco smokers. Our work focuses upon the physical interaction of NNK diazonium ion with DNA. This species is implicated in the formation of pyridyloxobutyl adducts, reacting with DNA bases and phosphate groups. Past research has investigated the metabolic activation of NNK by various enzymes, subsequent adduct formation with DNA, and the role of these adducts in mutagenesis. We present the first study of the physical interaction of NNK diazonium ion with TP53 (exon 5), a frequently mutated human tumor suppressor gene. We identify physical binding sites found via free energy minimization in computational docking simulations. These structures represent local potential energy minima in this system and suggest plausible sites for adduct formation.

SUBMITTER: Deligkaris C

PROVIDER: S-EPMC6621204 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Physical binding of the tobacco smoke carcinogen NNK diazonium ion to the human tumor suppressor gene TP53 Exon 5.

Deligkaris Christos C Millam Evan E

Toxicology research 20190417 4

The tobacco smoke <i>N</i>-nitrosamine, NNK, is an important carcinogen. It has been shown to induce lung, liver, and pancreatic cancer in animals. Its metabolites are associated with lung cancer in tobacco smokers. Our work focuses upon the physical interaction of NNK diazonium ion with DNA. This species is implicated in the formation of pyridyloxobutyl adducts, reacting with DNA bases and phosphate groups. Past research has investigated the metabolic activation of NNK by various enzymes, subse ...[more]

PMID: 31367336

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