Cytosine methylation enhances mitomycin C crosslinking

Abstract

Mitomycin C (MC) is a powerful antitumor agent that targets the DNA sequence CpG. Because it is likely that this dinucleotide will contain 5-methylcytosine in vivo, we have compared the cross-linking efficiency of MC for DNA containing either 5-methylcytosine or normal cytosine embedded in random-sequence DNA oligomers. We have found that mitomycin C displays a small but significant preference for methylated DNA. Recognition of an abnormal methylation pattern in the DNA of transformed cells may therefore be one mechanism by which MC exerts its chemotherapeutic effects.

Cytosine methylation determines hot spots of DNA damage in the human P 53 gene

“…Methylation of cytosine also reduces formation of UV-induced (6-4) photoproducts (44,45). However, formation of mitomycin C monoadducts and crosslinks is enhanced 1.4-to 3-fold by methylation of CpG sequences (46,47).…”

Cytosine Methylation Enhances Mitoxantrone-DNA Adduct Formation at CpG Dinucleotides

“…The cytosine methylation therefore may facilitate a local structural change to DNA that enhances adduct formation at these methylated sites. It has previously been documented that cytosine methylation alters the local structure of duplex DNA, resulting in a conformational change (9,21) leading to what has recently been termed E-DNA (22), and it therefore appears that it is this structural change that may enhance the accessibility of mitoxantrone to methylated CpG sites. The structural change may serve to enhance the initial intercalation of mitoxantrone into DNA, causing an increased likelihood of covalent reaction.…”

“…This difference was attributed to either a local charge effect, rendering the N2 of the reactive guanine more nucleophilic, or to a local conformational change rendering it more accessible (9). A later study by Tomasz and co-workers (23) discovered that CpG methylation of the plasmid pBR322 enhanced mitomycin C cross-linking by 3-fold at low concentrations (5 M), 2-fold at 10 M, and less thereafter.…”

“…It is known that CpG dinucleotides are underrepresented in the genome with significant depletion of the doublet in ϳ99% of the genome in higher eukaryotes, whereas the remaining 1% contains CpG at the expected frequency (9,10). In mammalian species, these CpG dinucleotides are known to be highly methylated with 60 -90% methylation at the 5-position of cytosine, whereas only 3-5% of isolated cytosine residues occur as 5-methylcytosine (9,10). Control of the methylation status of cytosines plays a central role in regulating expression of genes during mammalian development (11).…”

Site-specific and photo-induced alkylation of DNA by a dimethylanthraquinone-oligodeoxynucleotide conjugate

“…The major site of target alkylation was identified by a method of hydroxyl radical footprinting that had previously been used to characterize numerous interstrand reactions (13,40,41). This radical provides a non-specific method of strand scission via oxidation of the phosphoribose backbone.…”