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Cisplatin Reacts with Histone H1 and the Adduct Forms Ternary Complex with DNA

Abstract

Cisplatin is a widely used anticancer drug in clinic; it induces the apoptosis of cancer cells by targeting DNA. Nevertheless, the interaction with proteins has been found crucial in modulating the pre and post-target activity. The nuclear DNA is tightly assembled with histone proteins to form nucleosomes in chromatin, which could impede the drug to access DNA. On the other hand, the linker histone H1 is considered as ‘the gate to nucleosomal DNA’, due to its exposed location and dynamic conformation; therefore, this protein could influence the platination of DNA. In this work, we performed the reaction of cisplatin with histone H1 and investigated the interaction of the H1/cisplatin adduct with DNA. The reactions were conducted on the N-terminal domains of H1.4 (sequence 1-90, H1N90) and H1.0 (sequence 1-7, H1N7). Results showed that H1 readily reacts with cisplatin and generates bidentate and tridentate adducts, with methionine and glutamate residues as preferential binding sites. Chromatographic and NMR analyses showed that the platination rate of H1 is slightly higher than that of DNA and that platinated H1 can form H1-cisplatin-DNA ternary complexes with DNA. Interestingly, cisplatin is more prone to form H1-Pt-DNA ternary complexes than trans-oriented platinum agents. The formation of H1-cisplatin-DNA ternary complexes and the preference of cis- over trans-oriented platinum agents suggest an important role for histone H1 in the mechanism of action of cisplatin.

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Publication details

The article was received on 11 Dec 2018, accepted on 08 Jan 2019 and first published on 08 Jan 2019


Article type: Paper
DOI: 10.1039/C8MT00358K
Citation: Metallomics, 2019, Accepted Manuscript
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    Cisplatin Reacts with Histone H1 and the Adduct Forms Ternary Complex with DNA

    L. Cheng, C. Li, Z. Xi, K. wei, S. Yuan, F. Arnesano, G. Natile and Y. Liu, Metallomics, 2019, Accepted Manuscript , DOI: 10.1039/C8MT00358K

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