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Sci Adv. 2018 Nov 7;4(11):eaav2131. doi: 10.1126/sciadv.aav2131. eCollection 2018 Nov.

Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins.

Author information

1
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
2
Biology Faculty, Lomonosov Moscow State University, 119992 Moscow, Russia.
3
Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany.
4
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
5
Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
6
Department of Bioinformatics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
7
Department of Physics and Astronomy and Center for Quantitative Biology, Rutgers University, Piscataway, NJ 08854, USA.
8
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia.

Abstract

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).

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