Abstract
The histone chaperone FACT plays important roles in essentially every chromatin-associated process and is an important indirect target of the curaxin class of anti-cancer drugs. Curaxins are aromatiс compounds that intercalate into DNA and can trap FACT in bulk chromatin, thus interfering with its distribution and its functions in cancer cells. Recent studies have provided mechanistic insight into how FACT and curaxins cooperate to promote unfolding of nucleosomes and chromatin fibers, resulting in genome-wide disruption of contact chromatin domain boundaries, perturbation of higher order chromatin organization, and global disregulation of gene expression. Here, we discuss the implications of these insights for cancer biology.
Highlights
Facilitates chromatin transcription (FACT) is a highly conserved histone chaperone that participates in multiple physiological processes[1] including transcription[2,3,4,5,6,7,8], DNA replication[9,10,11,12,13], DNA repair[14,15,16,17], www.jcmtjournal.comChang et al
FACT is a heterodimer of the suppressor of Ty 16 (Spt16) protein and the structure-specific recognition protein 1 (SSRP1) in mammals or the polymerase one binding protein 3 (Pob3) in yeast[1,8,9,20,21]
DNA-binding domain; yeast FACT functionally interacts with the non-histone protein 6 (Nhp6) that consists of a single HMG box[22,23,24]
Summary
Facilitates chromatin transcription (FACT) is a highly conserved histone chaperone that participates in multiple physiological processes[1] including transcription[2,3,4,5,6,7,8], DNA replication[9,10,11,12,13], DNA repair[14,15,16,17], www.jcmtjournal.comChang et al. Curaxins induce chromatin trapping (c-trapping) of FACT in less than 1 min after addition to cells, and strongly inhibit normal human FACT activities in vivo[35]. The nucleosome unfolding activity of yeast FACT working together with Nhp6 protein that has been detected in vitro likely plays a role in nucleosome destabilization and/or histone removal at promoter regions[2,30].
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