Cisplatin fastens nucleosomal DNA under physiological salt conditions
2019.07 Single-molecule biophysics conference
Cisplatin is one of the most potent anti-cancer drugs, displaying clinical activity against various tumors. It is known that cisplatin binds to DNA and induces local kinks[1], which can lead to cell death[2]. The working mechanism of cisplatin has, however, not been fully understood yet. It is accepted that cisplatin delivery into a cell and its activity on DNA depends on local ionic states of cisplatin which is regulated by the ambient concentration of Cl−. In reality, other cellular anionic species also suppress cisplatin activity[3,4]. Moreover, recent studies highlighted several intriguing roles of histones in cisplatin’s anti-cancer effect[5-7]. Here we investigated these issues via magnetic tweezers. The reduced activity of cisplatin under physiological salt conditions is still sufficient to impair the integrity of a nucleosome by retaining its condensed structure firmly, even against severe mechanical and chemical disturbances. The cisplatin induced fastening of nucleosomal DNA can hamper DNA repair and inhibit nucleosome remodeling required for normal biological functions. Our direct physical measurements on cisplatin-nucleosome adducts suggest that formation of such adducts can be the key to the anti-cancer effect by cisplatin under physiological salt conditions and provide a new insight into understanding the mechanism of platinum-based anti-cancer drugs.
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