DNA demethylation protects from cleavable complex stabilization and DNA strand breakage induced by the topoisomerase type I inhibitor camptothecin.

Methylation of cytosine in CpG sequences of the DNA in mammalian cells is an epigenetic feature regulated very exactly that bears importance for events like gene expression, DNA replication, transcription and genetic imprinting. Changes in the DNA methylation pattern, both hypermethylation and hypomethylation, have been observed in the carcinogenic process. These changes, in general, influence the DNA conformation in such a way that certain proteins are disturbed in their interactions with the molecule. In this paper, we investigated in cultured Chinese hamster ovary cells the influence of hypomethylation induced by the substitution of 5-aza-2'-deoxycytidine for cytidine in DNA on topoisomerase type I (topo I) function, measured as the capacity of the enzyme inhibitor camptothecin (CPT) to stabilize the topoisomerase-DNA complexes and to induce DNA strand breakage. Our results demonstrate that the degree of methylation in DNA correlates with the effectiveness of CPT to stabilize the topo I-DNA complexes and to induce DNA cleavage. A protective effect of hypomethylation, as a whole, has been observed.