The histone chaperone FACT modulates nucleosome structure by tethering its components

Wang, Tao; Liu, Yang; Edwards, Garrett; Krzizike, Daniel D.; Scherman, Hataichanok; Luger, Karolin

doi:10.1101/309708

Cited by 21 publications

(41 citation statements)

References 47 publications

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“…Our current model of FACT function is consistent with published structural studies that showed that mammalian FACT could only bind nucleosomal components or partially disassembled nucleosomes (e.g., lacking the H2A/H2B dimer) because the FACT binding epitopes are hidden within the folded nucleosome (Tsunaka et al 2016;Safina et al 2017;Wang et al 2018). It is also consistent with studies in yeast that showed that FACT is targeted to transcribed chromatin through its recognition of RNA polymerase-disrupted nucleosomes (Martin et al 2018) If the above model is correct, why is transcription increased following the loss of FACT?…”

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

“…Several groups recently reported that mammalian FACT could not bind the folded nucleosome (Tsunaka et al 2016;Safina et al 2017;Wang et al 2018), which makes it difficult to explain how FACT can remove the nucleosomal barrier for transcription and replication. However, FACT can bind destabilized nucleosomes or nucleosomes with unwrapped DNA, which was shown in cells and cell-free systems (Tsunaka et al 2016;Safina et al 2017;Wang et al 2018). In addition, several previous reports showed that mutation of the FACT subunits in yeast or depletion of the subunits from human HeLa cells was accompanied by histone loss from transcribed regions (Morillo-Huesca et al 2010;Myers et al 2011;Carvalho et al 2013;Erkina and Erkine 2015;Feng et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Prevention of chromatin destabilization by FACT is crucial for malignant transformation

Sandlesh

Safina

Goswami

et al. 2018

Preprint

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Expression of histone chaperone FACT is increased in tumors and associated with poor prognosis. We investigated why aggressive tumor cells need FACT using a model where FACT could be turned off and confirmed that while FACT is not essential for non-tumor cells, cells become dependent on FACT following oncogene-induced transformation. We compared the phenotypic and transcriptional changes induced by FACT loss and excluded a direct role for FACT in the transcription of genes essential for the viability of transformed cells. Moreover, we established that in immortalized and transformed cells, FACT has a weak negative effect on gene expression. At the same time, we observed a positive correlation between FACT enrichment and the rate of transcription, which was consistent with previous reports. To explain these puzzling observations, we hypothesized that FACT does not facilitate transcription elongation in transformed cells, but prevents nucleosome loss associated with transcription. Indeed, we observed destabilization of chromatin in immortalized and transformed cells upon FACT loss. Furthermore, transformed cells had less stable chromatin than nontransformed cells, which made them vulnerable to FACT loss. However, the mechanisms of cell death upon chromatin destabilization needs to be established. Our data suggest that malignant transformation is accompanied by general chromatin destabilization, and FACT prevents irredeemable chromatin loss.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prevention of chromatin destabilization by FACT is crucial for malignant transformation

Sandlesh

Safina

Goswami

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…The structural changes that occur in canonical nucleosomes upon FACT binding are likely key to addressing this question, as the observed stimulation is specific to nucleosomal substrates. FACT can reorganize the nucleosome by disrupting histone/DNA contacts, leaving the nucleosome in an "open" or "destabilized" state (Chen et al, 2018;Kemble et al, 2015;McCullough et al, 2011) and by fully displacing H2A/H2B heterodimers (Belotserkovskaya et al, 2003;Chen et al, 2018;Hsieh et al, 2013;Orphanides et al, 1999;Wang et al, 2018;Xin et al, 2009a). The most straightforward explanation for the effect of FACT on Ubp10 activity is that FACT increases H2B deubiquitination by evicting H2A/H2B-Ub heterodimers, which are an excellent substrate for Ubp10 (Figures 2A and 3C).…”

Section: Discussionmentioning

confidence: 99%

FACT and Ubp10 collaborate to modulate H2B deubiquitination and nucleosome dynamics

Nune

Morgan

Connell

et al. 2018

Preprint

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Monoubiquitination of histone H2B (H2B-Ub) plays a role in transcription and DNA replication, and is required for normal localization of the histone chaperone, FACT.In yeast, H2B-Ub is deubiquitinated by Ubp8, a subunit of SAGA, and Ubp10. Although they target the same substrate, loss of Ubp8 and Ubp10 causes different phenotypes and alters the transcription of different genes. We show that Ubp10 has poor activity on yeast nucleosomes, but that addition of FACT stimulates Ubp10 activity on nucleosomes and not on other substrates. Consistent with a role for FACT in deubiquitinating H2B in vivo, a FACT mutant strain shows elevated levels of H2B-Ub.Combination of FACT mutants with deletion of Ubp10, but not Ubp8, confers increased sensitivity to hydroxyurea and activates a cryptic transcription reporter, suggesting that FACT and Ubp10 may coordinate nucleosome assembly during DNA replication and transcription. Our findings reveal unexpected interplay between H2B deubiquitination and nucleosome dynamics.

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“…FACT can remove one H2A-H2B dimer during reorganization and deposit it onto the H3-H4 tetramer or nucleosome hexamer in vitro [184,185]. A recent study demonstrated that FACT itself could not disassemble nucleosomes in vitro [186]. Moreover, DNA replication initiation was delayed when the FACT-MCM2-7 interaction was disrupted [173].…”

Section: Mcm2: Vanguard Of Nucleosome Disassembly and Parental Histonmentioning

confidence: 99%

The replisome guides nucleosome assembly during DNA replication

Zhang

Feng

2020

Cell Biosci

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Nucleosome assembly during DNA replication is tightly coupled to ongoing DNA synthesis. This process, termed DNA replication-coupled (RC) nucleosome assembly, is essential for chromatin replication and has a great impact on both genome stability maintenance and epigenetic inheritance. This review discusses a set of recent findings regarding the role of replisome components contributing to RC nucleosome assembly. Starting with a brief introduction to the factors involved in nucleosome assembly and some aspects of the architecture of the eukaryotic replisome, we discuss studies from yeast to mammalian cells and the interactions of replisome components with histones and histone chaperones. We describe the proposed functions of replisome components during RC nucleosome assembly and discuss their impacts on histone segregation and implications for epigenetic inheritance.

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The histone chaperone FACT modulates nucleosome structure by tethering its components

Cited by 21 publications

References 47 publications

Prevention of chromatin destabilization by FACT is crucial for malignant transformation

Prevention of chromatin destabilization by FACT is crucial for malignant transformation

FACT and Ubp10 collaborate to modulate H2B deubiquitination and nucleosome dynamics

The replisome guides nucleosome assembly during DNA replication

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