Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Structural Perturbation of Chromatin by Plant Alkaloid Sanguinarine and Its Functional Consequences
The hallmark of chromatin lies in its dynamic alteration of epigenetic marks, which regulates the gene expression and thereby, cellular homeostasis. Any small molecule compound that perturbs the chromatin structure could potentially alter the epigenetic state and hence, could be used for therapeutic purposes. Here, we report the structural perturbation of chromatin at different levels by DNA-binding plant alkaloid, Sanguinarine with potential as anticancer agent. Association of Sanguinarine with different levels of chromatin structure (chromatin, mononucleosome, and chromosomal DNA) was found to be enthalpically driven with micromolar dissociation constant. Comparative analysis of heat capacity change (ΔCp) accompanying sanguinarine-polymer interactions, results from dynamic light scattering studies, confocal and atomic force microscopic studies, and other biochemical studies indicate chromatin aggregation and nucleosomal instability with DNA release. Also, we are able to show that Sanguinarine modulates the epigenetic marks leading to the repression of histone modifications. It occurs via association of Sanguinarine with core histone. Sanguinarine inhibits histone acetylation both in vitro as well as in vivo. Remarkably, it does not affect the in vitro transcription from DNA template, but represses acetylation dependent chromatin transcription. These data establish for the first time that an anticancer DNA binding intercalator might play dual roles as inhibitor of transcription in chromatin and a modulator of chromatin modifying enzymes via perturbation of chromatin structure.
Suman Kalyan Pradhan1,*