Book of Abstracts: Albany 2005
Effect of Association of Anticancer Antibiotics Upon Chromatin Structure
Anticancer antibiotics, like chromomycinA3, mithramycin, and daunomycin, inhibit replication and transcription via reversible association with DNA. In eukaryotes the nuclear DNA is associated with different proteins in chromatin, the transcription machinery. We have been studying the association of these drugs with different levels of chromatin structure in order to understand their mode of action as transcription inhibitors inside the nucleus. Along with native chromatin and nucleus, we have examined their association with H1 depleted chromatin as a model for transcriptionally active chromatin. We have also examined the effect of the N-terminal tails of the core histones in the nucleosome upon the accessibility of these drugs to the nucleosomal DNA. The results of these studies can be summed up as follows. The antibiotics bind to both linker and nucleosomal DNA. They induce stabilization of the H1 histone-DNA contacts and leads to a slow aggregation of the native chromatin. In their presence, the accessibility of transcription factors to the linker DNA might be hindered. The association with nucleosome leads to a slow release of the nucleosomal DNA. The DNA release extent and kinetics depend upon the mode of binding of the drugs to the nucleosomal DNA. Removal of the N-terminal tails of the core histones enhances the accessibility of the drugs to the nucleosome. We propose that the tail domains not only regulate the eukaryotic transcription but also reduce the binding potential of xenobiotics like anticancer drugs to eukaryotic genome. Summing up, our studies show that the transcription inhibitory property of these small molecules cannot assessed from their DNA-binding property alone. On the other hand, the effect upon the chromatin and the nucleosome structure should be considered to understand the molecular basis of the action of these drugs in the nucleus.