Effect of Nucleosome Assembly on Alkylation by a Dynamic Electrophile

Shane R. Byrne, Kun Yang, Steven E. Rokita

Research output: Contribution to journalArticle

Abstract

Quinone methides are reactive electrophiles that are generated during metabolism of various drugs, natural products, and food additives. Their chemical properties and cellular effects have been described previously, and now their response to packaging DNA in a nucleosome core is described. A model bisquinone methide precursor (bisQMP) was selected based on its ability to form reversible adducts with guanine N7 that allow for their redistribution and transfer after quinone methide regeneration. Assembly of Widom's 601 DNA with the histone octamer of H2A, H2B, H3, and H4 from Xenopus laevis significantly suppressed alkylation of the DNA. This result is a function of DNA packaging since addition of the octamer without nucleosome reconstitution only mildly protected DNA from alkylation. The lack of competition between nucleophiles of DNA and the histones was consistent with the limited number of adducts formed by the histones as detected by tryptic digestion and ultraperformance liquid chromatography-mass spectrometry. Only three peptide adducts were observed after reaction with a monofunctional analogue of bisQMP, and only two peptide adducts were observed after reaction with bisQMP. Histone reaction was also suppressed when reconstituted into the nucleosome core particle. However, bisQMP was capable of cross-linking the DNA and histones in moderate yields (∼20%) that exceeded expectations derived from reaction of cisplatin, nitrogen mustards, and diepoxybutane. The core histones also demonstrated a protective function against dynamic alkylation by trapping the reactive quinone methide after its spontaneous regeneration from DNA adducts.

Original languageEnglish (US)
Pages (from-to)917-925
Number of pages9
JournalChemical research in toxicology
Volume32
Issue number5
DOIs
StatePublished - May 20 2019

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Nucleosomes
Alkylation
Histones
DNA
DNA Packaging
Regeneration
Packaging
Mechlorethamine
Food Additives
Food additives
Peptides
DNA Adducts
Xenopus laevis
Guanine
Nucleophiles
Biological Products
Liquid Chromatography
Liquid chromatography
Cisplatin
Digestion

ASJC Scopus subject areas

  • Toxicology

Cite this

Effect of Nucleosome Assembly on Alkylation by a Dynamic Electrophile. / Byrne, Shane R.; Yang, Kun; Rokita, Steven E.

In: Chemical research in toxicology, Vol. 32, No. 5, 20.05.2019, p. 917-925.

Research output: Contribution to journalArticle

Byrne, Shane R. ; Yang, Kun ; Rokita, Steven E. / Effect of Nucleosome Assembly on Alkylation by a Dynamic Electrophile. In: Chemical research in toxicology. 2019 ; Vol. 32, No. 5. pp. 917-925.
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