Mechanism of curaxin-dependent nucleosome unfolding by FACT
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 and trapping of FACT in the chromatin of cancer cells (c-trapping) through an unknown molecular mechanism....
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.1048117/full |
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| author | Olesya I. Volokh Anastasia L. Sivkina Andrey V. Moiseenko Andrey V. Moiseenko Anna V. Popinako Maria G. Karlova Maria E. Valieva Maria E. Valieva Maria E. Valieva Elena Y. Kotova Mikhail P. Kirpichnikov Timothy Formosa Vasily M. Studitsky Vasily M. Studitsky Olga S. Sokolova |
| author_facet | Olesya I. Volokh Anastasia L. Sivkina Andrey V. Moiseenko Andrey V. Moiseenko Anna V. Popinako Maria G. Karlova Maria E. Valieva Maria E. Valieva Maria E. Valieva Elena Y. Kotova Mikhail P. Kirpichnikov Timothy Formosa Vasily M. Studitsky Vasily M. Studitsky Olga S. Sokolova |
| author_sort | Olesya I. Volokh |
| collection | DOAJ |
| description | 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 and trapping of FACT in the chromatin of cancer cells (c-trapping) through an unknown molecular mechanism. Here, we analyzed the effects of curaxin CBL0137 on nucleosome unfolding by FACT using spFRET and electron microscopy. By itself, FACT adopted multiple conformations, including a novel, compact, four-domain state in which the previously unresolved NTD of the SPT16 subunit of FACT was localized, apparently stabilizing a compact configuration. Multiple, primarily open conformations of FACT-nucleosome complexes were observed during curaxin-supported nucleosome unfolding. The obtained models of intermediates suggest “decision points” in the unfolding/folding pathway where FACT can either promote disassembly or assembly of nucleosomes, with the outcome possibly being influenced by additional factors. The data suggest novel mechanisms of nucleosome unfolding by FACT and c-trapping by curaxins. |
| first_indexed | 2024-04-13T09:31:29Z |
| format | Article |
| id | doaj.art-c3e88a4384e64cfd8196406fe7b52a80 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-13T09:31:29Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-c3e88a4384e64cfd8196406fe7b52a802022-12-22T02:52:15ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-11-01910.3389/fmolb.2022.10481171048117Mechanism of curaxin-dependent nucleosome unfolding by FACTOlesya I. Volokh0Anastasia L. Sivkina1Andrey V. Moiseenko2Andrey V. Moiseenko3Anna V. Popinako4Maria G. Karlova5Maria E. Valieva6Maria E. Valieva7Maria E. Valieva8Elena Y. Kotova9Mikhail P. Kirpichnikov10Timothy Formosa11Vasily M. Studitsky12Vasily M. Studitsky13Olga S. Sokolova14Biology Faculty Lomonosov Moscow State University, Moscow, RussiaBiology Faculty Lomonosov Moscow State University, Moscow, RussiaBiology Faculty Lomonosov Moscow State University, Moscow, RussiaSemenov Federal Research Center of Chemical Physics RAS, Moscow, RussiaBach Institute of Biochemistry Research Center of Biotechnology of the Russian Academy of Sciences, Moscow, RussiaBiology Faculty Lomonosov Moscow State University, Moscow, RussiaBiology Faculty Lomonosov Moscow State University, Moscow, RussiaRG Development & Disease Max Planck Institute for Molecular Genetics, Berlin, GermanyInstitute for Medical and Human Genetics Charité-Universitätsmedizin Berlin, Berlin, GermanyFox Chase Cancer Center, Philadelphia, PA, United StatesBiology Faculty Lomonosov Moscow State University, Moscow, RussiaDepartment of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, United StatesBiology Faculty Lomonosov Moscow State University, Moscow, RussiaFox Chase Cancer Center, Philadelphia, PA, United StatesBiology Faculty Lomonosov Moscow State University, Moscow, RussiaHuman FACT (FACT) is a multifunctional histone chaperone involved in transcription, replication and DNA repair. Curaxins are anticancer compounds that induce FACT-dependent nucleosome unfolding and trapping of FACT in the chromatin of cancer cells (c-trapping) through an unknown molecular mechanism. Here, we analyzed the effects of curaxin CBL0137 on nucleosome unfolding by FACT using spFRET and electron microscopy. By itself, FACT adopted multiple conformations, including a novel, compact, four-domain state in which the previously unresolved NTD of the SPT16 subunit of FACT was localized, apparently stabilizing a compact configuration. Multiple, primarily open conformations of FACT-nucleosome complexes were observed during curaxin-supported nucleosome unfolding. The obtained models of intermediates suggest “decision points” in the unfolding/folding pathway where FACT can either promote disassembly or assembly of nucleosomes, with the outcome possibly being influenced by additional factors. The data suggest novel mechanisms of nucleosome unfolding by FACT and c-trapping by curaxins.https://www.frontiersin.org/articles/10.3389/fmolb.2022.1048117/fullSPT16FACTSSRP1nucleosometransmission electron microscopySpFRET microscopy |
| spellingShingle | Olesya I. Volokh Anastasia L. Sivkina Andrey V. Moiseenko Andrey V. Moiseenko Anna V. Popinako Maria G. Karlova Maria E. Valieva Maria E. Valieva Maria E. Valieva Elena Y. Kotova Mikhail P. Kirpichnikov Timothy Formosa Vasily M. Studitsky Vasily M. Studitsky Olga S. Sokolova Mechanism of curaxin-dependent nucleosome unfolding by FACT Frontiers in Molecular Biosciences SPT16 FACT SSRP1 nucleosome transmission electron microscopy SpFRET microscopy |
| title | Mechanism of curaxin-dependent nucleosome unfolding by FACT |
| title_full | Mechanism of curaxin-dependent nucleosome unfolding by FACT |
| title_fullStr | Mechanism of curaxin-dependent nucleosome unfolding by FACT |
| title_full_unstemmed | Mechanism of curaxin-dependent nucleosome unfolding by FACT |
| title_short | Mechanism of curaxin-dependent nucleosome unfolding by FACT |
| title_sort | mechanism of curaxin dependent nucleosome unfolding by fact |
| topic | SPT16 FACT SSRP1 nucleosome transmission electron microscopy SpFRET microscopy |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.1048117/full |
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