FACT in Cell Differentiation and Carcinogenesis

Hsieh, Fu-Kai; Kulaeva, Olga I.; Orlovsky, Igor V.; Studitsky, Vasily M.

doi:10.18632/oncotarget.356

Cited by 8 publications

(8 citation statements)

References 16 publications

(17 reference statements)

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“…Interestingly, FACT is frequently upregulated in undifferentiated aggressive tumors, indicating a potential role as an anti-cancer target (49–51). A well-studied drug, Curaxin, is toxic to cancer cells by simultaneously suppressing NF-kB and activating p53, resulting in the “chromatin trapping” of FACT (50).…”

Section: Discussionmentioning

confidence: 99%

SSRP1 Cooperates with PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming

Gao

Wei

et al. 2017

Cancer Research

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DNA single strand breaks (SSB) are the most common form of DNA damage, requiring repair processes that to initiate must overcome chromatin barriers. The FACT complex comprised of the SSRP1 and SPT16 proteins are important for maintaining chromatin integrity, with SSRP1 acting as an histone H2A/H2B chaperone in chromatin disassembly during DNA transcription, replication and repair. In this study, we show that SSRP1 but not SPT16 is critical for cell survival after ionizing radiation or methyl methanesulfonate-induced single-strand DNA damage. SSRP1 is recruited to SSB in PARP-dependent manner and retained at DNA damage sites by N-terminal interactions with the DNA repair protein XRCC1. Mutational analyses showed how SSRP1 function is essential for chromatin decondensation and histone H2B exchange at sites of DNA strand breaks, which are both critical to prime chromatin for efficient SSB repair and cell survival. By establishing how SSRP1 facilitates SSB repair, our findings provide a mechanistic rationale to target SSRP1 as a general approach to selectively attack cancer cells.

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Section: Discussionmentioning

confidence: 99%

SSRP1 Cooperates with PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming

Gao

Wei

et al. 2017

Cancer Research

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“…Therefore, FACT plays crucial roles in both transcriptional initiation and elongation, and hence, functional impairment of FACT would alter transcription and cellular growth. FACT is found to be upregulated in cancers, especially aggressive and poorly differentiated tumors, and its downregulation leads to tumor cell death (12)(13)(14). Thus, FACT has been suggested to be an attractive therapeutic target.…”

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confidence: 99%

Fine-Tuning of FACT by the Ubiquitin Proteasome System in Regulation of Transcriptional Elongation

Sen

Ferdoush

Kaja

et al. 2016

Molecular and Cellular Biology

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FACT (facilitates chromatin transcription), an evolutionarily conserved histone chaperone involved in transcription and other DNA transactions, is upregulated in cancers, and its downregulation is associated with cellular death. However, it is not clearly understood how FACT is fine-tuned for normal cellular functions. Here, we show that the FACT subunit Spt16 is ubiquitylated by San1 (an E3 ubiquitin ligase) and degraded by the 26S proteasome. Enhanced abundance of Spt16 in the absence of San1 impairs transcriptional elongation. Likewise, decreased abundance of Spt16 also reduces transcription. Thus, an optimal level of Spt16 is required for efficient transcriptional elongation, which is maintained by San1 via ubiquitylation and proteasomal degradation. Consistently, San1 associates with the coding sequences of active genes to regulate Spt16's abundance. Further, we found that enhanced abundance of Spt16 in the absence of San1 impairs chromatin reassembly at the coding sequence, similarly to the results seen following inactivation of Spt16. Efficient chromatin reassembly enhances the fidelity of transcriptional elongation. Taken together, our results demonstrate for the first time a fine-tuning of FACT by a ubiquitin proteasome system in promoting chromatin reassembly in the wake of elongating RNA polymerase II and transcriptional elongation, thus revealing novel regulatory mechanisms of gene expression. In eukaryotes, DNA is packaged into nucleosomes to form chromatin. Each nucleosome within chromatin consists of ϳ147 bp of DNA wrapped around a histone octamer containing one histone H3-H4 tetramer and two histone H2A-H2B dimers (1). Thus, chromatin structure plays crucial functions in regulation of DNA transactions such as transcription, replication, and DNA repair (2-4). A variety of factors are involved in altering chromatin structure and, hence, DNA transactions. These factors are generally classified as ATP-independent histone modifying enzymes, ATP-dependent chromatin remodelers, and histone chaperones. Histone modifying enzymes function through addition or removal of specific chemical groups (e.g., acetyl, methyl, ubiquitin, phospho, and SUMO), while ATP-dependent chromatin remodelers alter DNA-histone interactions or the composition of the nucleosome in an ATP-dependent manner. On the other hand, histone chaperones function by binding with nucleosomes or histones to facilitate assembly and/or disassembly of nucleosomes in an ATP-independent fashion. The histone chaperone that was first found to alter chromatin structure during transcription is FACT (facilitates chromatin transcription), which is evolutionarily conserved among eukaryotes (5, 6). In budding yeast (Saccharomyces cerevisiae), FACT is composed of Spt16 (suppressor of Ty) and Pob3 and physically interacts with nucleosomes with the assistance of the HMG (high mobility group) protein Nhp6. Likewise, FACT is also a heterodimer of Spt16 and SSRP1 (structurespecific recognition protein 1) in humans. SSRP1 contains HMG domain, while HMG domain is p...

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“…Histone chaperone FACT (facilitates chromatin transcription) is involved in DNA transcription (1)(2)(3)(4)(5)(6), replication (7)(8)(9)(10) and repair (11)(12)(13)(14)(15), cell differentiation, and cancer development (16)(17)(18)(19) [reviewed in (20)]. Human FACT (hFACT) is a heterodimer composed of two proteins: SPT16 (suppressor of Ty16) and SSRP1 (structurespecific recognition protein 1) (21).…”

Section: Introductionmentioning

confidence: 99%