Cisplatin reacts with histone H1 and the adduct forms a ternary complex with DNA

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Cisplatin is a widely used anticancer drug that induces cancer cell apoptosis by targeting DNA.
• Histone proteins package DNA into chromatin, potentially hindering cisplatin's access to its DNA target.
• Linker histone H1, due to its accessible and dynamic nature, may influence DNA platination by cisplatin.

Purpose of the Study:

• To investigate the reaction between cisplatin and histone H1.
• To examine the interaction of H1-cisplatin adducts with DNA.
• To elucidate the role of histone H1 in cisplatin's mechanism of action.

Main Methods:

• Reaction of cisplatin with N-terminal domains of histone H1 variants (H1.4 and H1.0).
• Chromatographic and Nuclear Magnetic Resonance (NMR) analyses to study adduct formation and platination rates.
• Investigation of H1-cisplatin-DNA ternary complex formation.

Main Results:

• Histone H1 readily reacts with cisplatin, forming bidentate and tridentate adducts, with preferential binding at methionine and glutamate residues.
• The platination rate of H1 by cisplatin is comparable to, and slightly higher than, that of DNA.
• Platinated H1 forms ternary complexes with cisplatin and DNA (H1-cisplatin-DNA), with a preference for cisplatin over trans-oriented platinum agents.

Conclusions:

• Histone H1 directly interacts with cisplatin, forming adducts.
• The formation of H1-cisplatin-DNA ternary complexes indicates a significant role for histone H1 in cisplatin's interaction with chromatin.
• Histone H1's involvement suggests a modulation of cisplatin's anticancer activity through protein-drug interactions.