| Aberrant methylation patterns have long been known to exist in the promoter regions of key regulatory genes in the DNA of tumor cells. However, the mechanisms by which these methylation patterns become altered during the transformation of normal cells to tumor cells have remained elusive. The studies presented here expand the role of DNA damage in the development of cancer to include epigenetic changes in addition to genetic mutations. The data show that oxidative lesions within the CpG dinucleotide inhibit both methyl-CpG binding proteins and methyltransferase activity, potentially interfering with the control of gene expression and the fidelity of methylation pattern transfer from parent to progeny. Alternately, inflammation-mediated halogenated cytosine damage products can mimic endogenous 5-methylcytosine in directing enzymatic DNA methylation, allowing for the establishment and propagation of aberrant methylation patterns. These halogenated damage products also enhance the binding of methyl-binding proteins promoting aberrant binding and can therefore interfere with chromatin organization and gene expression. The repair activity against these damage products was also investigated. Although some excision repair activity was found against 5-substituted pyrimidines, activity against 5-chlorocytosine was undetectable. Studies with DNA repair glycosylases reveal that local helix stability is an important determinant of base recognition by DNA repair enzymes; however, halogenated pyrimidines do not significantly alter duplex stability and can potentially accumulate within the DNA. This potential mechanism by which DNA damage interferes with sequence specific DNA-protein interactions important for epigenetic control, thereby altering cytosine methylation and epigenetic signaling, may provide a explanation for the association between inflammation and human cancer. |
