Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins

Han Wen Chang, Maria E. Valieva, Alfiya Safina, Razvan V. Chereji, Jianmin Wang, Olga I. Kulaeva, Alexandre V. Morozov, Mikhail P. Kirpichnikov, Alexey V. Feofanov, Katerina V. Gurova, Vasily M. Studitsky

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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).

Original languageEnglish (US)
Article numbereaav2131
JournalScience Advances
Volume4
Issue number11
DOIs
StatePublished - Nov 7 2018

All Science Journal Classification (ASJC) codes

  • General

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