Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins

Human FACT (facilitates chromatin transcription) is a multifunctional protein complex that has histone chaperone activity and facilitates nucleosome survival and transcription through chromatin. Anticancer drugs curaxins induce FACT trapping on chromatin of cancer cells (c-trapping), but the mechani...

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Bibliographic Details
Published in:Science advances 2018-11, Vol.4 (11), p.eaav2131
Main Authors: Chang, Han-Wen, Valieva, Maria E, Safina, Alfiya, Chereji, Răzvan V, Wang, Jianmin, Kulaeva, Olga I, Morozov, Alexandre V, Kirpichnikov, Mikhail P, Feofanov, Alexey V, Gurova, Katerina V, Studitsky, Vasily M
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Cancer
Carbazoles - pharmacology
Chromatin Assembly and Disassembly - drug effects
Chromatin Assembly and Disassembly - physiology
Fibrosarcoma - drug therapy
Fibrosarcoma - genetics
Fluorescence Resonance Energy Transfer
Histones - genetics
Histones - metabolism
Humans
Nucleosomes - genetics
Nucleosomes - metabolism
Promoter Regions, Genetic
Protein Binding
SciAdv r-articles
Transcription, Genetic - drug effects
Tumor Cells, Cultured
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Summary:Human FACT (facilitates chromatin transcription) is a multifunctional protein complex that has histone chaperone activity and facilitates nucleosome survival and transcription through chromatin. Anticancer drugs curaxins induce FACT trapping on chromatin of cancer cells (c-trapping), but the mechanism of c-trapping is not fully understood. Here, we show that in cancer cells, FACT is highly enriched within the bodies of actively transcribed genes. Curaxin-dependent c-trapping results in redistribution of FACT from the transcribed chromatin regions to other genomic loci. Using a combination of biochemical and biophysical approaches, we have demonstrated that FACT is bound to and unfolds nucleosomes in the presence of curaxins. This tight binding to the nucleosome results in inhibition of FACT-dependent transcription in vitro in the presence of both curaxins and competitor chromatin, suggesting a mechanism of FACT trapping on bulk nucleosomes (n-trapping).
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aav2131