Structure and function of the histone chaperone FACT – Resolving FACTual issues

Abstract

FAcilitates Chromatin Transcription (FACT) has been considered essential for transcription through chromatin mostly based on cell-free experiments. However, FACT inactivation in cells does not cause a significant reduction in transcription. Moreover, not all mammalian cells require FACT for viability. Here we synthesize information from different organisms to reveal the core function(s) of FACT and propose a model that reconciles the cell-free and cell-based observations. We describe FACT structure and nucleosomal interactions, and their roles in FACT-dependent transcription, replication and repair. The variable requirements for FACT among different tumor and non-tumor cells suggest that various FACT-dependent processes have significantly different levels of relative importance in different eukaryotic cells. We propose that the stability of chromatin, which might vary among different cell types, dictates these diverse requirements for FACT to support cell viability. Since tumor cells are among the most sensitive to FACT inhibition, this vulnerability could be exploited for cancer treatment.

Establishment and Maintenance of Chromatin Architecture Are Promoted Independently of Transcription by the Histone Chaperone FACT and H3-K56 Acetylation in Saccharomyces cerevisiae

“…FACT is essential for viability in many organisms, which has been attributed to central roles in both transcription and replication (Formosa 2012). However, emerging evidence indicates that differentiated cells of higher organisms remain viable and transcriptionally active without FACT (Gurova et al 2018), and that its dominant role might involve maintaining the existing chromatin landscape and promoting transitions to new ones during cell fate changes (Shen et al 2018). Our results support the importance of cooperation between FACT and H3-K56 status in establishing and maintaining chromatin architecture, but leave open questions regarding which physiological processes are impacted by this collaboration.…”

The FACT Histone Chaperone: Tuning Gene Transcription in the Chromatin Context to Modulate Plant Growth and Development

“…Moreover, SSRP1 and SPT16 genetically interact with TFIIS encoding a modulator of RNAPII activity and with HUB1/2, encoding factors catalysing elongation-related mono-ubiquitination of histone H2B (Lolas et al, 2010;Antosz et al, 2017). Taken together these findings indicate a role of Arabidopsis FACT in RNAPII transcriptional elongation (Van Lijsebettens and Grasser, 2014;Zhou et al, 2015;Grasser and Grasser, 2018), in line with the function of FACT as regulator of mRNA synthesis in other organisms (Reinberg and Sims, 2006;Formosa, 2012;Gurova et al, 2018), although the exact mechanism in vivo is still obscure.…”

“…Its name originates from the finding that FACT promoted in vitro transcription from reconstituted chromatin templates by destabilising nucleosomes, facilitating RNA polymerase II passage during elongation (Orphanides et al, 1998;Orphanides et al, 1999;Belotserkovskaya et al, 2003). Over the years it became clear that besides chromatin transcription, FACT is also involved in other chromatin-dependent processes such as replication, recombination, and repair (Belotserkovskaya et al, 2004;Singer and Johnston, 2004;Formosa, 2012;Gurova et al, 2018), and hence, the established name may well stand more broadly for facilitates chromatin transactions. FACT is a heterodimer consisting of the SSRP1 (Structure-Specific Recognition Protein 1; termed Pob3 in yeast) and SPT16 (SuPpressor of Ty 16).…”

“…Following transient nucleosome destabilisation, for instance, during passage of transcribing RNA polymerase II, FACT promotes nucleosome reassembly that is important to maintain proper chromatin signature and to prevent aberrant transcriptional initiation from cryptic promoters (Kaplan et al, 2003;Mason and Struhl, 2003;Cheung et al, 2008;Jamai et al, 2009;Wang et al, 2018). Further intriguing molecular and structural details of numerous studies on yeast and metazoan FACT are summarised in various excellent review articles (Belotserkovskaya et al, 2004;Formosa, 2012;Gurova et al, 2018).…”

“…SSRP1 contains an N-terminal domain that mediates dimerisation with SPT16, a middle domain, an acidic domain, and a C-terminal HMG-box domain (Figure 1). Metazoan SSRP1 differs from the plant orthologues by a more pronounced C-terminal extension, while the fungal orthologues lack the HMG-box domain (Supplementary Figure S2) that in yeast is provided by separate small HMGB-box proteins termed Nhp6a/b (Formosa, 2012;Gurova et al, 2018). Proteins closely related to Arabidopsis SSRP1 and SPT16 are encoded by monocot and dicot plants, as well as by Selaginella and Physcomitrella (Figure 2).…”