The p23 Molecular Chaperone and GCN5 Acetylase Jointly Modulate Protein-DNA Dynamics and Open Chromatin Status

Abstract

SUMMARY Cellular processes function through multi-step pathways that are reliant on the controlled association and disassociation of sequential protein complexes. While dynamic action is critical to propagate and terminate work, the mechanisms used to disassemble biological structures are not fully understood. Here, we show that the p23 molecular chaperone initiates disassembly of protein-DNA complexes and that the GCN5 acetyltransferase prolongs the dissociated state through lysine acetylation. By modulating the DNA bound-state, we found that the conserved and essential joint activities of p23 and GCN5 impacted transcription factor activation potential and response time to an environmental cue. Notably, p23 and GCN5 were required to maintain open chromatin regions along the genome indicating that dynamic protein behavior is a critical feature of various DNA-associated events. Our data support a model in which p23 and GCN5 regulate diverse multi-step pathways by controlling the longevity of protein-DNA complexes.

Lysine Deacetylases Regulate the Heat Shock Response Including the Age-Associated Impairment of HSF1

“…Besides phosphorylation, HSF1 is acetylated, sumoylated, and ubiquitinated [11]. While the significances of these modifications are not completely understood, lysine acetylation within the DNA binding domain can inhibit DNA interactions whereas acetylation of the central regulatory domain deters degradation of HSF1 [12], [13], and [14]. Hence, modification of select HSF1 lysines is a potent means to control the HSR and support cell vitality.…”

“…Prior studies have shown that the GCN5 acetyltransferase selectively targets HSF1 lysine 80 (K80), which stabilizes HSF1 to DNA, whereas K80 is one of many residues modified by the P300 acetyltransferase [13] and [14]. In either case, acetylation of K80 impedes HSF1 DNA binding activity and limits the HSR.…”

“…Intertwined within the acetylation process controlling transcription factor DNA binding activities is the p23 molecular chaperone [13]. Before the lysines coordinating DNA interactions can be acetylated p23 must dissociate the DNA-bound complex, as DNA binding conceals the target lysine [13].…”

“…Before the lysines coordinating DNA interactions can be acetylated p23 must dissociate the DNA-bound complex, as DNA binding conceals the target lysine [13]. The involvement of p23 in transcription factor acetylation events was founded in a synthetic genetic array linking the chaperone to both acetylases and deacetylases along with the discovery that the loss of p23 triggers increased expression of GCN5 and HDAC1 [13] and [16].…”

Heat shock in the springtime

“…Two SIRT1 regulatory factors, AROS and DBC1, also affect HSF1 acetylation status and activation, broadening the acetylation regulatory network (Raynes et al 2013). Brian Freeman (University of Illinois, Urbana-Champaign, USA) presented both sides of the coin, documenting roles for both deacetylation and histone (more appropriately termed lysine) acetyltransferases (HATs/KATs) (Zelin et al 2012). In vitro acetylation was shown to block DNA binding by HSF1, and overexpression of the KAT GCN5 reduced hsp70 expression in human cells, consistent with prior data.…”