The p23 Molecular Chaperone and GCN5 Acetylase Jointly Modulate Protein-DNA Dynamics and Open Chromatin Status
Open accessAbstract
Cellular processes function through multistep 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 multistep pathways by controlling the longevity of protein-DNA complexes.
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PTGES3 is reported to have a cytosolic HSP90-dependent protein chaperone function for steroid nuclear receptors.
“PTGES3 is reported to have a cytosolic HSP90-dependent protein chaperone function for steroid nuclear receptors”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [44]
The Results section (‘p23 and GCN5 Associate Independent of Established Cofactors’; page not given) says p23 is typically considered an HSP90 cochaperone. The Introduction describes cytosolic glucocorticoid receptors, but our copy does not establish that p23’s chaperone function for steroid nuclear receptors is cytosolic and HSP90-dependent. (LLM, conf=0.78)
Experimental — accuracy not yet measuredPTGES3 protein is reported to have several protein functions and to be localized to both the cytosol and nucleus.
“PTGES3 protein is reported to have several protein functions and to be localized to both the cytosol and nucleus41–49 (Fig. 3f).”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [44]
The Results section, “p23 and GCN5 Associate Independent of Established Cofactors” (page unavailable), identifies p23 as an HSP90 cochaperone and detects it in nuclear extracts. Other Results passages describe its roles in regulating GCN5 activity and protein–DNA binding. Our copy does not establish localization in the cytosol, so the claim about both locations is only partly supported. (LLM, conf=0.85)
Experimental — accuracy not yet measuredNuclear PTGES3 interacts with histone acetyltransferase KAT2A by co-IP western.
“Consistent with a previous report44, among the transcriptional regulators p300, KAT2A and FOXA1, nuclear PTGES3 interacts with histone acetyltransferase KAT2A by co-IP western (Extended Data Fig. 8b).”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [44]
PTGES3 has been reported to localize to the nucleus and previous publications showed nuclear PTGES3 is a glucocorticoid receptor co-factor that modulates GR activity in the nucleus at GR response elements.
“PTGES3 has also been reported to localize to the nucleus and previous publications showed nuclear PTGES3 is a glucocorticoid receptor (GR) co-factor that modulates GR activity in the nucleus at GR response elements44,45.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [44]
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Hsp90@chromatin.nucleus: an emerging hub of a networker
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“Of note, consistent with a role of these enzymes in modulating GR binding, overexpression of GCN5 results in a reduced activation of endogenous GR target genes and reduced DNA binding of GR (40).”
BackgroundLysine Deacetylases Regulate the Heat Shock Response Including the Age-Associated Impairment of HSF1
Zelin, E., & Freeman, B. (2015) · Journal of Molecular Biology · doi:10.1016/j.jmb.2015.02.010 · Cited by 54 · see citing works
“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].”
BackgroundInfluentialSelf-citationMolecular Mechanisms of Heat Shock Factors in Cancer
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“However, the histone de-acetylases SIRT1, HDAC7, and HDAC9 can reduce acetylation of HSF1, thereby prolonging the activation phase of the heat shock response [48,49].”
BackgroundEchtenkamp, F., Gvozdenov, Z., Adkins, N. L., Zhang, Y., Lynch-Day, M. A., Watanabe, S., Peterson, C. L., & Freeman, B. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.09.040 · Cited by 47 · see citing works
“Given the genetic links between both chaperones and RSC subunits, along with the functional dependence of chromatin on p23 (Wilson et al., 2006; Zelin et al., 2012), we felt that the RSC complex served as an ideal model to understand how molecular chaperones modulate an assembled multi-subunit protein structure.”
BackgroundMethodInfluentialSelf-citationCo-chaperone p23 Regulates C. elegans Lifespan in Response to Temperature
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“This finding is consistent with observation the p23-HSP90 complex has been shown to inhibit the activity of the HSF-1 complex in other systems [23,25].”
Mechanism of Long-Range Chromosome Motion Triggered by Gene Activation
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“As p23 regulates the DNA occupancy of numerous transcription factors (Zelin et al., 2012), we checked whether this was occurring at INO1.”
BackgroundSelf-citationHSFs, Stress Sensors and Sculptors of Transcription Compartments and Epigenetic Landscapes
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Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery
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“It is a member of the SAGA coactivator complex that regulates POLII-mediated transcription (Grant et al., 1999), and it has been shown to acetylate several nonhistone targets (Jacob et al., 2001; Lerin et al., 2006; Conacci-Sorrell et al., 2010; Zelin et al., 2012; L. Li et al., 2015).”
BackgroundHSF1 and Its Role in Huntington’s Disease Pathology
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“p23 does not harbor any obvious DNA-binding domains and it appears that its effect on transcription factors and chromatin is therefore mediated through protein-protein interactions with chromatin remodelers, such as the histone acetyltransferase GCN5 [54].”
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Highly Multiplexed RNA Aptamer Selection using a Microplate-based Microcolumn Device
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“Consistent with a previous report 44 , among the transcriptional regulators p300, KAT2A and FOXA1, nuclear PTGES3 interacts with histone acetyltransferase KAT2A by co-IP western (Extended Data Fig.”
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p23 and Aha1: Distinct Functions Promote Client Maturation
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HSF1 Regulation in Aging and Its Role in Longevity
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TRiC/CCT chaperonin governs RNA polymerase II activity in the nucleus to support RNA homeostasis
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HDAC1 is involved in the destabilization of the HSF2 protein under nonstress and stress conditions
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Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency
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Heat Shock Factor (HSF): The Promoter of Chaperone Genes. A Mini Review
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“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).”
Emergence and Characterization of the p23 Molecular Chaperone
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“Importantly, a further extension of the carboxyl-terminus is critical for the chaperone activity of p23 used both to prevent the aggregation of model substrates in vitro and to affect clients in vivo [61, 79–81].”
BackgroundInfluentialSelf-citationdaf-41/p23: A Small Protein Heating Up Lifespan Regulation
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“Hsp90 is known to regulate transcriptional outputs by influencing the activity of dozens of transcription factors via their cellular stability. p23, likewise, has been shown to influence the activity of transcription factors, including steroid hormone receptors and HSF-1 [23].”
BackgroundInfluentialInformation-sharing models for computational genetics
Edwards, M. D. (2016) · DSpace@MIT (Massachusetts Institute of Technology)
- Authors
- Zelin, E., Zhang, Y., Toogun, O. A., Zhong, S., & Freeman, B. C.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Freeman, Brian C.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 48
- Issue
- 3
- Pages
- 459-470
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3496002
- OpenAlex
- W2076711719
- Cited by
- 46
- References
- 50
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 4 · 2013: 3
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP2OD007417)
- National Cancer Institute (R01CA155333, CA155333)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074270, DK074270)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- lysine acetylation, open chromatin, transcription factor activation, chromatin dynamics
- MeSH terms
- Prostaglandin-E Synthases, Heat Shock Transcription Factors, p300-CBP-Associated Factor, Acetylation, Animals, Cells, Cultured, Chromatin, DNA, DNA-Binding Proteins, Embryo, Mammalian, Fibroblasts, HeLa Cells, Humans, Models, Genetic, Mutation, Protein Binding, Saccharomyces cerevisiae, Transcription Factors, Immunoblotting, Gene Expression, Mice, Knockout, Molecular Chaperones, Intramolecular Oxidoreductases, Reverse Transcriptase Polymerase Chain Reaction, Saccharomyces cerevisiae Proteins, p300-CBP Transcription Factors, Mice, Histone Acetyltransferases
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