Effect of Histone Lysine Methylation on DNA Lesion Reactivity in Nucleosome Core Particles

Kun Yang, Carsten Prasse, Marc M. Greenberg

Research output: Contribution to journalArticle

Abstract

Lysine methylation is a common post-translational histone modification that regulates transcription and gene expression. The lysine residues in the histone tail also react with damaged nucleotides in chromatin, including abasic sites and N7-methyl-2′-deoxyguanosine, the major product of DNA methylating agents. Lysine monomethylation transforms the ϵ-amine into a secondary amine, which could be more nucleophilic and/or basic than the ϵ-amine in lysine, and therefore more reactive with damaged DNA. The effect of lysine methylation on the reactivity with abasic sites and N7-methyl-2′-deoxyguanosine was examined in nucleosome core particles using a methylated lysine analogue derived from cysteine. ϵ-Amine methylation increases the rate constant for abasic site reaction within nucleosome core particles. Reactivity at the two positions examined increased less than twofold. Mechanistic experiments indicate that faster β-elimination from an intermediate iminium ion accounts for accelerated abasic reactivity. The rate constants for nucleophilic attack (Schiff base/iminium ion formation) by the lysine and methylated lysine analogues are indistinguishable. Similarly, the rate constants describing nucleophilic attack by the lysine and methylated lysine analogues on β-2′-fluoro-N7-methyl-2′-deoxyguanosine to form DNA-protein cross-links are also within experimental error of one another. These data indicate that abasic site containing DNA will be destabilized by lysine methylation. However, these experiments do not indicate that DNA-protein cross-link formation, a recently discovered form of damage resulting from N7-guanine methylation, will be affected by this post-translational modification.

Original languageEnglish (US)
Pages (from-to)910-916
Number of pages7
JournalChemical research in toxicology
Volume32
Issue number5
DOIs
StatePublished - May 20 2019

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Methylation
Nucleosomes
DNA Methylation
Histones
Lysine
DNA
Deoxyguanosine
Amines
Rate constants
Post Translational Protein Processing
Histone Code
Ions
Schiff Bases
Guanine
Transcription
Gene expression
Chromatin
Cysteine
Proteins
Nucleotides

ASJC Scopus subject areas

  • Toxicology

Cite this

Effect of Histone Lysine Methylation on DNA Lesion Reactivity in Nucleosome Core Particles. / Yang, Kun; Prasse, Carsten; Greenberg, Marc M.

In: Chemical research in toxicology, Vol. 32, No. 5, 20.05.2019, p. 910-916.

Research output: Contribution to journalArticle

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