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Chang HW , Valieva ME , Safina A , Chereji RV , Wang J , Kulaeva OI , Morozov AV , Kirpichnikov MP , Feofanov AV , Gurova KV , Studitsky VM
Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins
Sci Adv. 2018 Nov;4(11) :eaav2131
PMID: 30417101    PMCID: PMC6221510    URL: https://www.ncbi.nlm.nih.gov/pubmed/30417101
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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).
2375-2548 Chang, Han-Wen Orcid: 0000-0003-1974-7246 Valieva, Maria E Safina, Alfiya Chereji, Razvan V Orcid: 0000-0002-0572-6412 Wang, Jianmin Kulaeva, Olga I Morozov, Alexandre V Kirpichnikov, Mikhail P Feofanov, Alexey V Gurova, Katerina V Studitsky, Vasily M P30 CA016056/CA/NCI NIH HHS/United States R01 CA197967/CA/NCI NIH HHS/United States R01 GM119398/GM/NIGMS NIH HHS/United States R01 HG004708/HG/NHGRI NIH HHS/United States Journal Article United States Sci Adv. 2018 Nov 7;4(11):eaav2131. doi: 10.1126/sciadv.aav2131. eCollection 2018 Nov.