Mechanism of curaxin-dependent nucleosome unfolding by FACT

• DOI: 10.3389/fmolb.2022.1048117
• Publication Date: 2022-11-22T08:57:26Z
• Authors: Olesya I. Volokh; Anastasia L. Sivkina; Andrey V. Moiseenko; Anna V. Popinako; Maria G. Karlova; Maria E. Valieva; Elena Y. Kotova; Mikhail P. Kirpic...; Timothy Formosa; Vasily M. Studitsky; Olga S. Sokolova
• Keywords: Linker DNA; Chaperone (clinical); Cryo-Electron Microscopy; Chromatosome

Human FACT (FACT) is a multifunctional histone chaperone involved in transcription, replication and DNA repair. Curaxins are anticancer compounds that induce FACT-dependent nucleosome unfolding trapping of the chromatin cancer cells (c-trapping) through an unknown molecular mechanism. Here, we analyzed effects curaxin CBL0137 on by using spFRET electron microscopy. By itself, adopted multiple conformations, including novel, compact, four-domain state which previously unresolved NTD SPT16 subunit was localized, apparently stabilizing compact configuration. Multiple, primarily open conformations FACT-nucleosome complexes were observed during curaxin-supported unfolding. The obtained models intermediates suggest "decision points" unfolding/folding pathway where can either promote disassembly or assembly nucleosomes, with outcome possibly being influenced additional factors. data novel mechanisms c-trapping curaxins.