Molecular binding of formaldehyde to DNA and proteins Public Deposited

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  • March 20, 2019
Creator
  • Lu, Kun
    • Affiliation: College of Arts and Sciences, Department of Applied Physical Sciences, Materials Science Graduate Program
Abstract
  • Formaldehyde is produced worldwide on a large scale (21 million tons in 2000) and used in a wide spectrum of applications. Its toxicity and carcinogenic effects have evoked numerous public health concerns. According to the International Agency on Research on Cancer (IARC), formaldehyde is classified as a known animal and human carcinogen, causing nasal cancer. More limited epidemiologic evidence suggests that formaldehyde can also induce leukemia in humans, however, this is controversial. In this dissertation, we have designed an integrated bottom-up approach to address critical issues to better understand formaldehyde's carcinogenic potential. Specifically, the N-terminus of histone and lysine residues located in both the histone N-terminal tail and the globular fold domain were identified as binding sites for formaldehyde in the current study. We also found that formaldehyde-induced lysine adducts could inhibit the formation of post translational modifications on histone, raising the possibility that formaldehyde might alter epigenetic regulation. We have also elucidated the structures of DNA-protein crosslinks induced by formaldehyde. Detailed characterization of the formaldehyde-derived linkage of single amino acids with nucleosides by NMR and mass spectrometry established that these amino acids all form cross-links involving formation of a formaldehyde-derived methylene bridge. Our results also demonstrated that Lys-dG cross-links are the most common DNA-protein crosslinks induced by formaldehyde, however, they are very labile. The finding that Cys-CH2-dG cross-links could be initiated by the S-hydroxymethyl group of cysteine residue lead to the identification of a novel dG-CH2-GSH adduct. This adduct is unique because of the involvement of S-hydroxymethylglutathione, a key player in the detoxification of formaldehyde. After our extensive work on biomarker discovery and validation involving DNA monoadducts and DNA-DNA cross-links, we applied these methods to analyze DNA samples from rats exposed to [13CD2]-formaldehyde for 1 day and 5 days. The results show that exogenous formaldehyde induced N2-hydroxymethyl-dG monoadducts and dG-dG cross-links in DNA from rat nasal mucosa, but did not form [13CD2]-adducts in distant tissues despite analyzing 5 times more DNA than for nasal epithelium. These data provide strong evidence supporting a genotoxic and cytotoxic mode of action for inhaled formaldehyde in the target tissue for carcinogenesis, but do not support the biological plausibility that inhaled formaldehyde causes leukemia in rats.
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  • Swenberg, James A.
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