Binding of (MTR)2Zn2+ complex to chromatin: a comparison with (MTR)2Mg2+ complex

Mithramycin (MTR), a member of aureolic group of anticancer antibiotic, binds reversibly to double stranded DNA via minor groove with (G.C) base specificity. It leads to inhibition of replication and transcription. Results from different laboratories have shown that at and above physiological pH, Mg2+ is an obligatory factor for the DNA binding and subsequent transcription inhibitory property of mithramycin. Zn2+ is another physiologically important bivalent cation. Its coordination property leads to its important role as a cofactor in different enzymes and nucleosomal DNA binding proteins. Characterization of the complex between mithramycin and Zn2+ using spectroscopic methods shows that the drug forms single type of complex with Zn2+ in the mole ratio of 2:1 in terms of antibiotic: Zn2+. DNA binding properties of the (MTR)2Zn2+ complex has been studied using calf thymus DNA, rat liver chromatin and nucleosome core. (MTR)2Zn2+ complex binds to calf thymus DNA with affinity higher than the corresponding dimer complex with Mg2+ ion. The presence of histone proteins in chromatin and nucleosome reduces the accessibility and hence binding potential of (MTR)2Zn2+ complex to nucleosomal DNA. We have also examined the effect of (MTR)2Zn2+ complex upon the stability of nucleosome core particle. The complex disassembles nucleosome structure leading to the release of nucleosomal DNA. Significance of the results to understand the molecular basis of the action of the drug in vivo is discussed.