Cisplatin fastens chromatin irreversibly even at a high chloride concentration

• Published in: Nucleic acids research 2021-12, Vol.49 (21), p.12035-12047
• Main Authors: Moon, Hyeon-Min, Park, Jin-Sung, Lee, Il-Buem, Kang, Young-Im, Jung, Hae Jun, An, Dongju, Shin, Yumi, Kim, Min Ji, Kim, Hugh I, Song, Ji-Joon, Kim, Jaehoon, Lee, Nam-Kyung, Hong, Seok-Cheol
• Format: Article
• Language: English
• Subjects: Chemical Biology and Nucleic Acid Chemistry; Chromatin Assembly and Disassembly - drug effects; Cisplatin - pharmacology; Histones - metabolism; Membrane Proteins - metabolism; Neoplasms - drug therapy; Nucleosomes - metabolism
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkab922

Abstract Cisplatin is one of the most potent anti-cancer drugs developed so far. Recent studies highlighted several intriguing roles of histones in cisplatin's anti-cancer effect. Thus, the effect of nucleosome formation should be considered to give a better account of the anti-cancer effect of cisplatin. Here we investigated this important issue via single-molecule measurements. Surprisingly, the reduced activity of cisplatin under [NaCl] = 180 mM, corresponding to the total concentration of cellular ionic species, is still sufficient to impair the integrity of a nucleosome by retaining its condensed structure firmly, even against severe mechanical and chemical disturbances. Our finding suggests that such cisplatin-induced fastening of chromatin can inhibit nucleosome remodelling required for normal biological functions. The in vitro chromatin transcription assay indeed revealed that the transcription activity was effectively suppressed in the presence of cisplatin. Our direct physical measurements on cisplatin-nucleosome adducts suggest that the formation of such adducts be the key to the anti-cancer effect by cisplatin. Graphical Abstract Graphical Abstract Cisplatin fastens chromatin irreversibly even at a high chloride concentration.