Histone chaperone FACT and curaxins: effects on genome structure and function

Chang, Han-Wen; Nizovtseva, Ekaterina V.; Razin, Sergey V.; Formosa, Tim; Gurova, Katerina V.; Studitsky, Vasily M.

doi:10.20517/2394-4722.2019.31

Cited by 15 publications

(13 citation statements)

References 94 publications

(139 reference statements)

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“…Cancer cells also tend to lack S phase progression and G2/M monitoring checkpoints, suggesting they would also be more sensitive than normal to decreased chromatin quality. Consistent with this, cancer cells often have aberrant patterns of histone modifications and altered higher order chromatin architecture, and the curaxins that block FACT function can disrupt this architecture more readily than they do in normal cells ( 29 ). FACT also appears to contribute to chromosome architecture more directly by influencing cohesin function ( 140 ).…”

Section: Why Is Fact Essential In Some Cells But Not Others?mentioning

confidence: 86%

“…Several recent reviews have focused on structural features of FACT and its roles in development and carcinogenesis ( 23–24 , 29 , 35 ). Here, we review results that support a broader role for FACT in balancing the construction and deconstruction of chromatin, and how this affects the regulation of transcription as well as other chromatin-centered processes including DNA replication and repair.…”

Section: Introductionmentioning

confidence: 99%

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The role of FACT in managing chromatin: disruption, assembly, or repair?

Formosa

Winston

2020

Nucleic Acids Research

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FACT (FAcilitates Chromatin Transcription) has long been considered to be a transcription elongation factor whose ability to destabilize nucleosomes promotes RNAPII progression on chromatin templates. However, this is just one function of this histone chaperone, as FACT also functions in DNA replication. While broadly conserved among eukaryotes and essential for viability in many organisms, dependence on FACT varies widely, with some differentiated cells proliferating normally in its absence. It is therefore unclear what the core functions of FACT are, whether they differ in different circumstances, and what makes FACT essential in some situations but not others. Here, we review recent advances and propose a unifying model for FACT activity. By analogy to DNA repair, we propose that the ability of FACT to both destabilize and assemble nucleosomes allows it to monitor and restore nucleosome integrity as part of a system of chromatin repair, in which disruptions in the packaging of DNA are sensed and returned to their normal state. The requirement for FACT then depends on the level of chromatin disruption occurring in the cell, and the cell's ability to tolerate packaging defects. The role of FACT in transcription would then be just one facet of a broader system for maintaining chromatin integrity.

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Section: Why Is Fact Essential In Some Cells But Not Others?mentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

The role of FACT in managing chromatin: disruption, assembly, or repair?

Formosa

Winston

2020

Nucleic Acids Research

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“…These changes in the structure of nucleosomal DNA were largely reversed by subsequent addition of an excess of competitor DNA that removes FACT from the complex. Thus, FACT induces a large-scale, reversible nucleosome unfolding in the presence of curaxin ( 16,22 ).…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Curaxin-dependent Nucleosome Unfolding by FACT

Volokh

Sivkina

Moiseenko

et al. 2022

Preprint

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Human FACT (FACT) is a multifunctional histone chaperone involved in transcription, replication and DNA repair. Curaxins are anticancer compounds that induce FACT- dependent nucleosome unfolding and trapping of FACT in the chromatin of cancer cells (c-trapping) through an unknown molecular mechanism. Here, we analyzed the effects of curaxin CBL0137 on nucleosome unfolding by FACT using spFRET and electron microscopy. By itself, FACT adopted multiple conformations, including a novel, compact, four-domain state in which the previously unresolved NTD of the SPT16 subunit of FACT was localized, apparently stabilizing a compact configuration. Multiple, primarily open conformations of FACT-nucleosome complexes were observed during curaxin-supported nucleosome unfolding. The structures of intermediates suggest “decision points” in the unfolding/folding pathway where FACT can either promote disassembly or assembly of nucleosomes, with the outcome possibly being influenced by additional factors. The data suggest novel mechanisms of nucleosome unfolding by FACT and c-trapping by curaxins.

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“…Intriguingly, curaxin, a powerful anti‐cancer compound has been shown to target the FACT complex trapping in onto chromatin. [ 115 ] It remains to be established whether curaxin also affects histone H1 binding to chromatin and replication origin assembly.…”

Section: Implications For Cancer Biologymentioning

confidence: 99%

Epigenetic regulation of replication origin assembly: A role for histone H1 and chromatin remodeling factors

Falbo

Costanzo

2020

BioEssays

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During early embryonic development in several metazoans, accurate DNA replication is ensured by high number of replication origins. This guarantees rapid genome duplication coordinated with fast cell divisions. In Xenopus laevis embryos this program switches to one with a lower number of origins at a developmental stage known as mid-blastula transition (MBT) when cell cycle length increases and gene transcription starts. Consistent with this regulation, somatic nuclei replicate poorly when transferred to eggs, suggesting the existence of an epigenetic memory suppressing replication assembly origins at all available sites. Recently, it was shown that histone H1 imposes a non-permissive chromatin configuration preventing replication origin assembly on somatic nuclei. This somatic state can be erased by SSRP1, a subunit of the FACT complex. Here, we further develop the hypothesis that this novel form of epigenetic memory might impact on different areas of vertebrate biology going from nuclear reprogramming to cancer development.

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Histone chaperone FACT and curaxins: effects on genome structure and function

Cited by 15 publications

References 94 publications

The role of FACT in managing chromatin: disruption, assembly, or repair?

The role of FACT in managing chromatin: disruption, assembly, or repair?

Mechanism of Curaxin-dependent Nucleosome Unfolding by FACT

Epigenetic regulation of replication origin assembly: A role for histone H1 and chromatin remodeling factors

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