Discussion

DNA mutations, as well chromosome mis-segregation (aneugenicity)or breakage (clastogenicity), can be initiating events in the development of cancers. It is now clear that there also are changes “above” the genome which can produce mutant phenotypes. These ‘epigenetic’ changes fall into two main classes: modifications to the histone proteins around which DNA is coiled; changes to the methylation state of C residues in the DNA sequence. It is the latter are the focus of this presentation. In particular, regions of the genome rich in CpG dinucleotides (“CpG islands”). Our laboratory has previously reported that increased expression of the GADD45a gene in human cells is a signature of exposure to mutagens aneugens and clastogens (Hastwell et al Mutagenesis 2006). Interestingly, the gene has a “CpG” island that spanning the promoter and the first three exons. Its methylation in breast cancer tissues and U2OS cells down-regulates induction of apoptosis, and makes them less responsive to genotoxic drugs. Decitabine demethylates these GADD45a CpG sites in breast cells, restoring gene expression and drug sensitivity (Al-Romaih et al Neoplasia, 2008). This talk reports describes a study of the effects on global methylation status and GADD45a expression caused by exposure to DNA methyltransferase inhibitors in TK6 cells.