Examination of hypochlorous acid-induced damage to cytosine residues in a CpG dinucleotide in DNA

Joseph I. Kang, Lawrence Sowers

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Inflammation-mediated, neutrophil-derived hypochlorous acid can damage DNA and result in the chlorination damage products 5-chlorocytosine and 5-chlorouracil as well as the oxidation damage products 5-hydroxycytosine and 5-hydroxyuracil. While 5-chlorocytosine could potentially perturb epigenetic signals if formed at a CpG dinucleotide, the remaining products are miscoding and could result in transition mutations. In this article, we have investigated the reaction of hypochlorous acid with an oligonucleotide site-specifically enriched with 15N to probe the reactivity of cytosine at CpG. These experiments demonstrate directly the formation of 5-chlorocytosine at a CpG dinucleotide in duplex DNA. We observe that chlorination relative to oxidation damage is greater at CpG by a factor of approximately two, whereas similar amounts of 5-chlorocytosine and 5-hydroxycytosine are formed at two non-CpG sites examined. The relative amounts of deamination of the cytosine to uracil derivatives are similar at CpG and non-CpG sites. Overall, we observe that the reactivity of cytosine at CpG and non-CpG sites toward hypochlorous acid induced damage is similar (5-chlorocytosine > 5-hydroxycytosine > 5-hydroxyuracil > 5-chlorouracil), with a greater proportion of chlorination damage at CpG sites. These results are in accord with the potential of inflammation-mediated DNA damage to both induce transition mutations and to perturb epigenetic signals.

Original languageEnglish (US)
Pages (from-to)1211-1218
Number of pages8
JournalChemical Research in Toxicology
Volume21
Issue number6
DOIs
StatePublished - Jun 2008
Externally publishedYes

Fingerprint

Hypochlorous Acid
Cytosine
Chlorination
Halogenation
DNA
Epigenomics
DNA Damage
Inflammation
Oxidation
Deamination
Mutation
Uracil
Oligonucleotides
Neutrophils
5-chlorocytosine
Derivatives
5-hydroxycytosine
Experiments

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Examination of hypochlorous acid-induced damage to cytosine residues in a CpG dinucleotide in DNA. / Kang, Joseph I.; Sowers, Lawrence.

In: Chemical Research in Toxicology, Vol. 21, No. 6, 06.2008, p. 1211-1218.

Research output: Contribution to journalArticle

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