Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins

Chang, Han-Wen; Валиева, М. Е.; Safina, Alfiya; Chereji, Răzvan V.; Wang, Jianmin; Kulaeva, Olga I.; Morozov, Alexandre V.; Kirpichnikov, Mikhaǐl P.; Feofanov, Аlexey V.; Gurova, Katerina V.; Studitsky, Vasily M.

doi:10.1126/sciadv.aav2131

Cited by 50 publications

(71 citation statements)

References 63 publications

(163 reference statements)

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“…To further investigate whether Ssrp1 represses other genes or TEs in ESCs, we analyzed the transcriptome of Ssrp1 −/− ESCs by RNA-seq. Surprisingly, more genes were upregulated (895 genes) than downregulated (213 genes) after the loss of Ssrp1 (Figure 3A and Supplementary Table S2 ), although Ssrp1 is traditionally associated with actively transcribed genes ( 53 ). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of Ssrp1 target genes identified downregulation of various cellular metabolic pathways related to the biosynthesis of amino acids, antibiotics and glycolysis whereas upregulated KEGG terms were enriched of pathways related to cell cycle, p53 signaling, viral infection and ubiquitination (Figure 3B and C ).…”

Section: Resultsmentioning

confidence: 99%

Histone chaperone FACT represses retrotransposon MERVL and MERVL-derived cryptic promoters

Chen

Zhang

Xie

et al. 2020

Nucleic Acids Research

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Endogenous retroviruses (ERVs) were usually silenced by various histone modifications on histone H3 variants and respective histone chaperones in embryonic stem cells (ESCs). However, it is still unknown whether chaperones of other histones could repress ERVs. Here, we show that H2A/H2B histone chaperone FACT plays a critical role in silencing ERVs and ERV-derived cryptic promoters in ESCs. Loss of FACT component Ssrp1 activated MERVL whereas the re-introduction of Ssrp1 rescued the phenotype. Additionally, Ssrp1 interacted with MERVL and suppressed cryptic transcription of MERVL-fused genes. Remarkably, Ssrp1 interacted with and recruited H2B deubiquitinase Usp7 to Ssrp1 target genes. Suppression of Usp7 caused similar phenotypes as loss of Ssrp1. Furthermore, Usp7 acted by deubiquitinating H2Bub and thereby repressed the expression of MERVL-fused genes. Taken together, our study uncovers a unique mechanism by which FACT complex silences ERVs and ERV-derived cryptic promoters in ESCs.

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Section: Resultsmentioning

confidence: 99%

Histone chaperone FACT represses retrotransposon MERVL and MERVL-derived cryptic promoters

Chen

Zhang

Xie

et al. 2020

Nucleic Acids Research

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“…Indirect inhibition of the FACT histone chaperone is the most well-studied activity of the curaxins 27,28,47 . Curaxin binding to DNA induces nucleosome destabilization genome-wide 27,47 , which, in turn, generates superhelical tension that cannot be relieved due to topoisomerase inhibition and induces B- to Z-DNA transitions 27 . During this process, multiple epitopes within the destabilized nucleosome become available for FACT binding.…”

Section: Discussionmentioning

confidence: 99%

The anti-cancer drugs curaxins target spatial genome organization

et al. 2019

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Recently we characterized a class of anti-cancer agents (curaxins) that disturbs DNA/histone interactions within nucleosomes. Here, using a combination of genomic and in vitro approaches, we demonstrate that curaxins strongly affect spatial genome organization and compromise enhancer-promoter communication, which is necessary for the expression of several oncogenes, including MYC . We further show that curaxins selectively inhibit enhancer-regulated transcription of chromatinized templates in cell-free conditions. Genomic studies also suggest that curaxins induce partial depletion of CTCF from its binding sites, which contributes to the observed changes in genome topology. Thus, curaxins can be classified as epigenetic drugs that target the 3D genome organization.

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“…After confirming the oncogenic function of FACT complex, we tested the therapeutic potential of Curaxin that binds to DNA, thereby trapping FACT complex in chromatin 29. We showed that HCC cells were highly sensitive to Curaxin treatment, whereas immortalised hepatocyte line MIHA was more tolerant to Curaxin compared with HCC cell lines (figure 8A,B), indicating that Curaxin selectively suppressed cancer cell growth.…”

Section: Resultsmentioning

confidence: 89%

Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression

Shen

Chen

Lee

et al. 2019

Gut

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ObjectiveFacilitates Chromatin Transcription (FACT) complex is a histone chaperone participating in DNA repair-related and transcription-related chromatin dynamics. In this study, we investigated its oncogenic functions, underlying mechanisms and therapeutic implications in human hepatocellular carcinoma (HCC).DesignWe obtained HCC and its corresponding non-tumorous liver samples from 16 patients and identified FACT complex as the most upregulated histone chaperone by RNA-Seq. We further used CRISPR-based gene activation and knockout systems to demonstrate the functions of FACT complex in HCC growth and metastasis. Functional roles and mechanistic insights of FACT complex in oxidative stress response were investigated by ChIP assay, flow cytometry, gene expression assays and 4sU-DRB transcription elongation assay. Therapeutic effect of FACT complex inhibitor, Curaxin, was tested in both in vitro and in vivo models.ResultsWe showed that FACT complex was remarkably upregulated in HCC and contributed to HCC progression. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilised NRF2 and FACT complex form a positive feedback loop; NRF2 transcriptionally activates the FACT complex, while FACT complex promotes the transcription elongation of NRF2 and its downstream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Therapeutically, Curaxin effectively suppressed HCC growth and sensitised HCC cell to sorafenib.ConclusionIn conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment.

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Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins

Abstract: Protumor factor FACT is removed from transcribed genes by anticancer drugs curaxins.

Cited by 50 publications

References 63 publications

Histone chaperone FACT represses retrotransposon MERVL and MERVL-derived cryptic promoters

Histone chaperone FACT represses retrotransposon MERVL and MERVL-derived cryptic promoters

The anti-cancer drugs curaxins target spatial genome organization

Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression

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