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J. Biol. Chem., Vol. 276, Issue 19, 15953-15960, May 11, 2001
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From the Department of Biochemistry, LaTrobe University,
Victoria 3086, Australia
Recently, we have shown that mitoxantrone can be
activated by formaldehyde in vitro to form DNA adducts that
are specific for CpG and CpA sites in DNA. The CpG specificity of
adduct formation prompted investigations into the effect of cytosine
methylation (CpG) on adduct formation, since the majority of CpG
dinucleotides in the mammalian genome are methylated and
hypermethylation in subsets of genes is associated with various
neoplasms. Upon methylation of a 512-base pair DNA fragment
(containing the lac UV5 promoter) using HpaII
methylase, three CCGG sites downstream of the promoter were methylated
at C5 of the internal cytosine residue. In vitro transcription studies of mitoxantrone-reacted DNA revealed a 3-fold enhancement in transcriptional blockage (and hence adduct formation) exclusively at these methylated sites. In vitro
cross-linking assays also revealed that methylation enhanced
mitoxantrone adduct formation by 2-3-fold, and methylation of cytosine
at a single potential drug binding site on a duplex oligonucleotide
also enhanced adduct levels by 3-fold. Collectively, these results
indicate preferential adduct formation at methylated CpG sites.
However, adducts at these methylated sites exhibited the same stability as nonmethylated sites, suggesting that cytosine methylation increases drug accessibility to DNA rather than being involved in kinetic stabilization of the adduct.
Cytosine Methylation Enhances Mitoxantrone-DNA Adduct
Formation at CpG Dinucleotides*
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom all correspondence should be addressed. Tel.: 61 3 94792182; Fax: 61 3 94792467; E-mail: d.phillips@latrobe.edu.au.
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