Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate
Open accessAbstract
Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymatic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex between an HDAC and a co-repressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor (also known as NCOR2). The structure reveals two remarkable features. First, the SMRT-DAD undergoes a large structural rearrangement on forming the complex. Second, there is an essential inositol tetraphosphate molecule--D-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P(4))--acting as an 'intermolecular glue' between the two proteins. Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P(4), which may act as a regulator--potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and opens the way to novel therapeutic opportunities.
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Claims the paper makes
25 of 36 cited sources checked · 6 supported · 2 flagged · accuracy not yet measured
- Premisecitation
Previous mutagenesis of SMRT-DAD showed that all mutations that failed to activate HDAC3 also abolished or significantly impaired interaction, including mutations of Lys449, Tyr470 and Tyr471, which play a key role in binding Ins(1,4,5,6)P4.
“These conclusions are supported by our previous mutagenesis study of the SMRT-DAD in which we looked at the effect of mutations on both the interaction with, and the deacetylase activity of, HDAC3. All mutations that failed to activate HDAC3 also abolished, or significantly impaired, interaction. These include mutations of Lys449, Tyr470 and Tyr471 which play a key role in binding the Ins(1,4,5,6)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [31] Codina, A. et al. Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 102, 6009–6014 (2005) source
Split into 2 atoms — 0 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation
HDACs 1, 2 and 3 require association with large multisubunit corepressor complexes for maximal activity.
“HDACs 1, 2 and 3 require association with large multisubunit corepressor complexes for maximal activity7-12.”
Quote in the paperSubstantial claim5 of 6 sources checked- cites [7] Zhang, Y. et al. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13, 1924–1935 (1999) source
The Abstract identifies HDAC1 and HDAC2 as components of the multisubunit Sin3 and NuRD complexes. Table 1 and the section on NuRD and DNA methylation show that adding MTA2 markedly increases the activity of an HDAC1/HDAC2-containing core complex. The paper does not establish the same requirement for HDAC3, so the claim extends beyond its findings. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [8] Li, J. et al. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19, 4342–4350 (2000) source
The section “SMRT and N-CoR complexes as a new class of HDAC-containing complexes” reports that HDAC3 is a stable component of large corepressor complexes, and “The majority of SMRT and N-CoR complexes may contain HDAC3” reports strong deacetylase activity in those complexes. The Introduction also describes an HDAC1/2-containing mSin3 complex. None of these passages establishes that association with a complex is required for maximal activity of HDACs 1, 2, and 3. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [9] Lechner, T. et al. Sds3 (suppressor of defective silencing 3) is an integral component of the yeast Sin3·Rpd3 histone deacetylase complex and is required for histone deacetylase activity. J. Biol. Chem. 275, 40961–40966 (2000) source
The introduction (page unavailable) describes HDACs as multiprotein complexes associated with repressors and corepressors. The Discussion (page unavailable) reports that a yeast Rpd3p complex loses deacetylase activity when Sds3p is absent. The paper does not establish that HDACs 1, 2, and 3 each require such complexes for maximal activity. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [10] Zhang, J., Kalkum, M., Chait, B. T. & Roeder, R. G. The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol. Cell 9, 611–623 (2002) source
- cites [11] Guenther, M. G., Barak, O. & Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 21, 6091–6101 (2001) source
The Results and Discussion show that HDAC3 needs SMRT or N-CoR for activity, and the Discussion reports that HDAC1 needs components of the NuRD complex. The copy does not establish the same requirement for HDAC2. Moreover, the Abstract says a purified SMRT domain is sufficient to activate HDAC3, so it does not establish that a large multisubunit complex is required for its activity. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [12] Wen, Y. D. et al. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 97, 7202–7207 (2000) source
The introduction describes HDAC1 and HDAC2 as components of multisubunit complexes, and the Results identify an enzymatically active HDAC3 complex. The Results also show that an N-CoR fragment increases HDAC3 activity, but do not establish that association with a large complex is required for maximal activity of all three enzymes; the same experiment found no enhancement of HDAC1 activity by that fragment. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Findingown data
The DAD-specific motif buries a surface of 1,178 Å2.
“Along with a further extended region, this DAD-specific motif buries a surface of 1,178Å2.”
Quote in the paperNot a substantial claim - Findingown data
The active site of HDAC3 lies at the base of a tunnel leading from the surface of the protein.
“The active site lies at the base of a tunnel leading from the surface of the protein.”
Quote in the paperNot a substantial claim - Findingown data
The HDAC3 region that interacts with SMRT-DAD differs between HDAC8 and HDAC3.
“This region differs between HDAC8 and HDAC3.”
Quote in the paperSubstantial claim
- Findingown data
A solvent exposed tyrosine residue unique to HDAC3 is located on the surface of the enzyme immediately adjacent to the active site tunnel.
“A solvent exposed tyrosine residue is located on the surface of the enzyme immediately adjacent to the active site tunnel. This tyrosine is unique to HDAC3”
Quote in the paperNot a substantial claim - Findingown data
The SMRT-DAD interacts with the amino terminal region of HDAC3 (residues 9-49) that forms helix H1, loop L2, helix H2 and strand S2.
“The SMRT-DAD interacts with the amino terminal region of HDAC3 (residues 9-49) that forms helix H1, loop L2, helix H2 and strand S2.”
Quote in the paperSubstantial claim - Findingnone given
In HDAC3, helix H1 is distorted and can only be considered a pseudo-helix.
“Indeed, in HDAC3, helix H1 is distorted and can only be considered to be a pseudo-helix.”
Quote in the paperSubstantial claim - Findingown data
The electron density difference map revealed a well-ordered small molecule bound at the interface between HDAC3 and the DAD.
“At the earliest stages of refinement, the electron density difference map revealed a well-ordered small molecule bound at the interface between HDAC3 and the DAD (figure 2A).”
Quote in the paperSubstantial claim - Findingown data
An acetate molecule bound at the active site makes hydrogen bonds to the catalytic zinc and side chains of Ty298 and His134.
“An acetate molecule (present during purification) is bound at the active site, making hydrogen bonds to the catalytic zinc and side chains of Ty298 and His134.”
Quote in the paperNot a substantial claim - Findingown data
HDAC3 and SMRT-DAD each contribute five hydrogen bonds and salt bridges to Ins(1,4,5,6)P4, involving His17, Gly21, Lys25, Arg265 and Arg301 from HDAC3 and Lys449, Tyr470, Tyr471, Lys474 and Lys475 from SMRT-DAD.
“HDAC3 and the SMRT-DAD each contribute five hydrogen bonds and salt bridges to the Ins(1,4,5,6)P4 (His17, Gly21, Lys25, Arg265 & Arg301 and Lys449, Tyr470, Tyr471, Lys474 & Lys 475 respectively) (figure 2E).”
Quote in the paperSubstantial claim - Findingown data
There is a key interaction between Ins(1,4,5,6)P4 and Arg265 in loop L6.
“There is a key interaction between the Ins(1,4,5,6)P4 and Arg265 in loop L6 (coloured orange in figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Comparison of HDAC3 with HDAC8 reveals that HDAC8 differs significantly in the region where HDAC3 interacts with SMRT-DAD and Ins(1,4,5,6)P4.
“Comparison of the HDAC3 structure with that of HDAC8, which does not require activation by complex formation, reveals that HDAC8 differs significantly in the region where HDAC3 interacts with the SMRT-DAD and Ins(1,4,5,6)P4 (figure 4D).”
Quote in the paperSubstantial claim - Findingown data
At the base of the cleft, the ζ-nitrogen atoms of SMRT Lys449 and HDAC3 Lys25 are just 4.4 Å from each other.
“Indeed, at the base of the cleft, the ζ–nitrogen atoms of SMRT Lys449 SMRT, and HDAC3 Lys25 are just 4.4Å from each other.”
Quote in the paperSubstantial claim - Findingown data
In the crystal, the active site of HDAC3 resembles a product complex.
“In the crystal, the active site of the HDAC3 resembles a product complex (figure 4A and B).”
Quote in the paperSubstantial claim - Findingown data
The binding surfaces for the DAD and Ins(1,4,5,6)P4 are located to one side of the HDAC3 active site, involving pseudo helix H1 and loops L1 and L6.
“The binding surfaces for the DAD and the Ins(1,4,5,6)P4 are located to one side of the HDAC3 active site involving pseudo helix H1 and the loops L1 and L6 (figure 4A,B,C).”
Quote in the paperSubstantial claim - Findingown data
Binding is highly specific for Ins(1,4,5,6)P4, since the electron density shows the ligand is uniquely Ins(1,4,5,6)P4 rather than a mixture of inositol phosphates.
“It is also striking that the binding is highly specific for Ins(1,4,5,6)P4 since the electron density shows that the ligand is uniquely Ins(1,4,5,6)P4 rather than a mixture of inositol phosphates.”
Quote in the paperSubstantial claim - Findingown data
Ins(1,4,5,6)P4 is sufficiently tightly bound to the complex that it is retained through the entire purification process.
“It is notable that the Ins(1,4,5,6)P4 is sufficiently tightly bound to the complex that it is retained through the entire purification process.”
Quote in the paperSubstantial claim - Findingown data
The key Ins(1,4,5,6)P4 binding residues are almost entirely conserved in the SANT domains of MTA and CoREST corepressor partners.
“The key Ins(1,4,5,6)P4 binding residues are almost entirely conserved (figure 3B).”
Quote in the paperSubstantial claim - Findingown data
A methionine sidechain from an adjacent SMRT-DAD in the crystal lattice is bound in the active site tunnel mimicking a lysine residue.
“Furthermore, a methionine sidechain (from an adjacent SMRT-DAD in the crystal lattice) is bound in the active site tunnel mimicking a lysine residue.”
Quote in the paperNot a substantial claim - Findingnone given
To retain an intact complex it was necessary to use low ionic strength buffers.
“However, to retain an intact complex it was necessary to use low ionic strength buffers.”
Quote in the paperSubstantial claim - Findingown data
The paper presents the first structure of a histone deacetylase in complex with its activating corepressor.
“We present the first structure of a histone deacetylase in complex with its activating corepressor.”
Quote in the paperSubstantial claim - Interpretationreasoning
The differences between HDAC8 and HDAC3 in the SMRT-DAD interaction region may explain why HDAC8 is active in the absence of an interacting corepressor.
“These differences may explain why HDAC8 is active in the absence of an interacting corepressor.”
Quote in the paperSubstantial claim - Interpretationreasoning
Ins(1,4,5,6)P4 binding is an essential requirement for the interaction between SMRT and HDAC3, acting as an intermolecular glue that cements the complex together.
“A careful examination of the structure suggests that Ins(1,4,5,6)P4 binding is an essential requirement for the interaction between SMRT and HDAC3 acting as a ‘intermolecular glue’ that cements the complex together.”
Quote in the paperSubstantial claim - Interpretationreasoning
Together these differences give substrate better access to the active site of HDAC8 than would be possible in uncomplexed HDAC3.
“We suggest that together these differences give substrate better access to that active site of HDAC8 than would be possible in the uncomplexed HDAC3.”
Quote in the paperSubstantial claim - Interpretationreasoning
It is likely that specificity for a particular HDAC is conferred by the region amino-terminal to the SANT domain, i.e. the DAD-specific motif in SMRT/NCoR and the ELM2 domains in MTA and CoREST proteins.
“It is likely that the specificity for the particular HDAC is conferred by the region amino-terminal to the SANT domain i.e. the DAD specific motif in SMRT/NCoR and the ELM2 domains in the MTA and CoREST proteins.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Given that the key residues are also found in the yeast HDAC Rpd3 and the Snt1 corepressor, the inositol phosphate activation mechanism appears evolutionarily conserved.
“and, given that the key residues are also found in the yeast HDAC, Rpd3, and the Snt1 corepressor, it would appear that this mechanism is also evolutionarily conserved.”
Quote in the paperSubstantial claim- Rests on an assumption: The key Ins(1,4,5,6)P4-binding residues are also found in the yeast HDAC Rpd3 and the Snt1 corepressor.
- Study design and conductown data
The pattern of crystallographic temperature factors for the various structures supports the interpretation of differences in substrate access.
“The pattern of crystallographic temperature factors for the various structures supports this interpretation (Supplementary figure 5).”
Quote in the paperSubstantial claim - Interpretationreasoning
Inositol phosphate activation of HDACs is a general mechanism.
“Taken together this suggests that inositol phosphate activation of HDACs is a general mechanism”
Quote in the paperSubstantial claim - Interpretationreasoning
If Ins(1,4,5,6)P4 were not present, the many basic residues on either side of the binding cleft would likely prevent interaction through charge repulsion.
“If the Ins(1,4,5,6)P4 ligand were not present, then the many basic residues on either side of the binding cleft would likely prevent interaction through charge repulsion.”
Quote in the paperSubstantial claim - Interpretationown data
The fact that Ins(1,4,5,6)P4 remained bound during purification suggests that it is a structural cofactor.
“The fact that Ins(1,4,5,6)P4 remained bound during purification would seem to suggest that it is a structural cofactor.”
Quote in the paperSubstantial claim - Interpretationown data
Ins(1,4,5,6)P4 is the physiologically relevant assembly partner.
“This supports the interpretation that Ins(1,4,5,6)P4 is the physiologically relevant assembly partner.”
Quote in the paperSubstantial claim - Interpretationreasoning
Consequently, in mammalian cells, a phosphatase is required to generate Ins(1,4,5,6)P4.
“Consequently, in mammalian cells, a phosphatase is required to generate Ins(1,4,5,6)P4.”
Quote in the paperSubstantial claim - Interpretationown data
These findings support the interpretation that Arg265 and loops L1 and L6 are important in the activation of HDAC3.
“These findings support our interpretation of the importance of these residues in the activation of HDAC3.”
Quote in the paperSubstantial claim
- May combine two claims. 31
- Classified as probably not a substantial claim. 11
May combine two claims.
PremisecitationThe most likely enzyme to generate Ins(1,4,5,6)P4 is PTEN, a well-known tumour suppressor gene that is active in the nucleus and plays a role in chromosome stability.
“The most likely enzyme is the well-known tumour suppressor gene PTEN42,43, which is known to be active in the nucleus and to play a role in chromosome stability (reviewed in44).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [42] Craxton, A., Caffrey, J. J., Burkhart, W., Safrany, S. T. & Shears, S. B. Molecular cloning and expression of a rat hepatic multiple inositol polyphosphate phosphatase. Biochem. J. 328, 75–81 (1997) source
The ‘Enzymic activity of recombinant MIPP’ section reports that MIPP converts Ins(1,3,4,5,6)P5 to a product consistent with Ins(1,4,5,6)P4. The Discussion identifies MIPP as an endoplasmic-reticulum protein, not nuclear PTEN. The paper does not make the attributed claim about PTEN or chromosome stability. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [43] Caffrey, J. J., Darden, T., Wenk, M. R. & Shears, S. B. Expanding coincident signaling by PTEN through its inositol 1,3,4,5,6-pentakisphosphate 3-phosphatase activity. FEBS Lett. 499, 6–10 (2001) source
- cites [44] Di Cristofano, A. & Pandolfi, P. P. The multiple roles of PTEN in tumor suppression. Cell 100, 387–390 (2000) source
The citation to this review is attached to the statement that PTEN is active in the nucleus and plays a role in chromosome stability. Our copy instead says that very little is known about PTEN’s subcellular localization (Abstract, page unavailable); searches for nuclear activity and chromosome stability found no passage addressing either point. The review does identify PTEN as a tumor suppressor, but that is not the part attributed to this citation. (LLM, conf=0.74)
Experimental — accuracy not yet measured
May combine two claims.
FindingcitationOverall the HDAC3 structure is similar to the previously determined class I HDAC structures of HDAC8 and HDAC2 and consists of an eight-stranded parallel beta-sheet surrounded by alpha-helices.
“Overall the HDAC3 structure is similar to the previously determined class I HDAC structures of HDAC834 and HDAC235 and consists of an eight-stranded parallel beta-sheet surrounded by a number of alpha-helices.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [34] Somoza, J. R. et al. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12, 1325–1334 (2004) source
- cites [35] Bressi, J. C. et al. Exploration of the HDAC2 foot pocket: synthesis and SAR of substituted N-(2-aminophenyl)benzamides. Bioorg. Med. Chem. Lett. 20, 3142–3145 (2010) source
May combine two claims.
PremisecitationSeveral further studies have supported the importance of Arg82 kinase activity in transcriptional regulation and chromatin remodelling, together suggesting that Ins(1,4,5,6)P4 has an important regulatory role in yeast.
“Several further studies have supported the importance of Arg82 kinase activity in transcriptional regulation and chromatin remodelling 37-39, together suggesting that Ins(1,4,5,6)P4 has an important regulatory role in yeast.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [37] Steger, D. J. Regulation of chromatin remodeling by inositol polyphosphates. Science 299, 114–116 (2003) source
The passage on the Arg82D131A mutant (section labeled Abstract; page unavailable) supports the importance of Arg82 kinase activity for PHO5 transcription and chromatin remodeling in budding yeast. The concluding passage suggests a role for IP4 and/or IP5, but does not identify Ins(1,4,5,6)P4 specifically; that part of the attributed claim is more specific than the paper supports. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [38] El Alami, M., Messenguy, F., Scherens, B. & Dubois, E. Arg82p is a bifunctional protein whose inositol polyphosphate kinase activity is essential for nitrogen and PHO gene expression but not for Mcm1p chaperoning in yeast. Mol. Microbiol. 49, 457–468 (2003) source
The Abstract reports that Arg82p kinase activity is required for regulation of nitrogen-responsive and PHO genes. The Discussion reports a role for Ins(1,4,5,6)P4 in chromatin remodelling, citing Steger et al. (2003), but this paper does not show that Arg82p kinase activity itself regulates chromatin remodelling; its own transcriptional findings point chiefly to inositol pyrophosphates. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [39] Shen, X., Xiao, H., Ranallo, R., Wu, W.-H. & Wu, C. Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates. Science 299, 112–114 (2003) source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIPMK, the mammalian homologue of Arg82, has been reported to phosphorylate Ins(1,4,5)P3 to form Ins(1,3,4,5,6)P4 and then Ins(1,3,4,5,6)P5.
“IPMK, the mammalian homologue of Arg82, has been reported to phosphorylate Ins(1,4,5)P3 to form Ins(1,3,4,5,6)P4 and then Ins(1,3,4,5,6)P540,41.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [40] Saiardi, A. et al. Mammalian inositol polyphosphate multikinase synthesizes inositol 1,4,5-trisphosphate and an inositol pyrophosphate. Proc. Natl Acad. Sci. USA 98, 2306–2311 (2001) source
The Results (page unavailable) show that mammalian IPMK converts Ins(1,4,5)P3 to Ins(1,3,4,5)P4 and then to Ins(1,3,4,5,6)P5. The cited sentence gives the intermediate as Ins(1,3,4,5,6)P4, which is not the intermediate reported in the paper. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [41] Nalaskowski, M. M., Deschermeier, C., Fanick, W. & Mayr, G. W. The human homologue of yeast ArgRIII protein is an inositol phosphate multikinase with predominantly nuclear localization. Biochem. J. 366, 549–556 (2002) source
May combine two claims.
PremisecitationThe DAD contains an extended SANT-like domain with an amino-terminal DAD-specific motif, and deletion of this motif results in both loss of binding and failure to activate HDAC3.
“The DAD contains an extended SANT-like domain with an amino-terminal DAD-specific motif. Deletion of this motif results in both loss of binding and failure to activate HDAC311.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] Guenther, M. G., Barak, O. & Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 21, 6091–6101 (2001) source
Classified as probably not a substantial claim.
PremisecitationOf the class I HDACs, only HDAC8 is a fully functional enzyme in isolation.
“Of these, only HDAC8 is a fully functional enzyme in isolation5,6.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [5] Hu, E. et al. Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor. J. Biol. Chem. 275, 15254–15264 (2000) source
The Results (page unavailable) show that HDAC8 purified to near homogeneity was enzymatically active. The Discussion (page unavailable) says this suggests activity without cofactors, but the paper does not establish that HDAC8 is the only class I HDAC functional in isolation. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [6] Lee, H., Rezai-Zadeh, N. & Seto, E. Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Mol. Cell. Biol. 24, 765–773 (2004) source
May combine two claims.
PremisecitationHDAC3 appears to be uniquely recruited to the SMRT/NCoR complex, where it interacts with a conserved deacetylase-activation-domain (DAD) within SMRT or NCoR.
“In contrast, HDAC3 appears to be uniquely recruited to the SMRT/NCoR complex where it interacts with a conserved deacetylase-activation-domain (DAD) within SMRT or NCoR8,10,12,24,25,26.”
Quote in the paperSubstantial claim5 of 6 sources checked- cites [8] Li, J. et al. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19, 4342–4350 (2000) source
The section “SMRT and N-CoR complexes as a new class of HDAC-containing complexes” establishes that HDAC3 is a stable subunit of both complexes, and “HDAC3 may interact directly with N-CoR” maps regions that interact with HDAC3. The paper does not identify a conserved deacetylase-activation domain (DAD) in either corepressor or establish that HDAC3 is uniquely recruited to these complexes; its discussion considers the recruitment of multiple HDACs. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [10] Zhang, J., Kalkum, M., Chait, B. T. & Roeder, R. G. The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol. Cell 9, 611–623 (2002) source
- cites [12] Wen, Y. D. et al. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 97, 7202–7207 (2000) source
The Discussion (page not available in our copy) describes an HDAC3–N-CoR/SMRT complex, and the Results show that HDAC3 binds N-CoR regions distinct from those used by other HDACs. The paper does not identify a conserved deacetylase-activation domain (DAD) in SMRT or N-CoR as the binding site; it instead reports binding to multiple N-CoR regions. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [24] Guenther, M. G. et al. A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev. 14, 1048–1057 (2000) source
The Abstract (page not provided) identifies HDAC3 in a purified core SMRT complex without other HDACs. “SMRT serves as a platform for HDAC3 and TBL1” (page not provided) reports direct HDAC3 interaction with SMRT RD2 and strong interaction with N-CoR RD2. The paper does not identify either region as a conserved deacetylase-activation domain (DAD), or establish that HDAC3 is uniquely recruited to SMRT/N-CoR complexes in general. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [25] Yoon, H.-G. et al. Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1. EMBO J. 22, 1336–1346 (2003) source
The section on TBL1/TBLR1–histone interactions states that SMRT and N-CoR interact directly with HDAC3 through a deacetylase-activating domain (DAD). But the Introduction and the section on HDAC3’s role describe HDAC3 as the primary or major associated HDAC, not the unique one; the Introduction also mentions associations with other HDACs. Our copy does not establish that the DAD is conserved. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [26] Oberoi, J. et al. Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery. Nature Struct. Mol. Biol. 18, 177–184 (2011) source
The introductory passage labelled Abstract (page unavailable) says HDAC3 is recruited to the SMRT/NCoR complex and interacts with the SMRT deacetylase activation domain. It also says the complexes associate with multiple histone deacetylases, so it does not establish that HDAC3 is uniquely recruited. The passage does not explicitly describe an interaction with the NCoR DAD. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationThe DAD both recruits and activates HDAC3.
“The DAD both recruits and activates HDAC310-12.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [10] Zhang, J., Kalkum, M., Chait, B. T. & Roeder, R. G. The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol. Cell 9, 611–623 (2002) source
- cites [11] Guenther, M. G., Barak, O. & Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 21, 6091–6101 (2001) source
- cites [12] Wen, Y. D. et al. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 97, 7202–7207 (2000) source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe previously reported structure of the isolated DAD from SMRT revealed that part of the DAD-specific motif forms an extra helix folded against the three helices of the SANT domain to form a four-helix bundle, and the amino-terminal portion of the DAD-specific motif is unstructured in solution.
“We have previously reported the structure of the isolated DAD from SMRT31. This revealed that part of the DAD-specific motif forms an extra helix that is folded against the three helices of the SANT domain to form a four-helix bundle. The amino-terminal portion of the DAD-specific motif is unstructured in solution31.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [31] Codina, A. et al. Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 102, 6009–6014 (2005) source
Classified as probably not a substantial claim.
PremisecitationHDAC3 and SMRT-DAD do not form a complex when expressed in bacterial cells.
“It has been proposed that the assembly of the HDAC3 and SMRT-DAD requires a chaperone complex, since when these proteins are expressed in bacteria they do not form a complex30.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Guenther, M. G. Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex. Genes Dev. 16, 3130–3135 (2002) source
The Conclusion (page not provided) proposes that TRiC primes HDAC3 to interact with SMRT, supporting the chaperone-complex part of the citing sentence. It discusses HDAC3 purified from insect cells, but does not report whether HDAC3 and SMRT-DAD form a complex when expressed in bacteria. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationRecruitment of HDAC3 to the DAD is essential for repression by certain nuclear receptors and for the maintenance of normal circadian physiology.
“Recruitment of HDAC3 to the DAD is essential for repression by certain nuclear receptors and for the maintenance of normal circadian physiology27-29.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [27] You, S.-H., Liao, X., Weiss, R. E. & Lazar, M. A. The interaction between nuclear receptor corepressor and histone deacetylase 3 regulates both positive and negative thyroid hormone action in vivo . Mol. Endocrinol. 24, 1359–1367 (2010) source
- cites [28] Ishizuka, T. & Lazar, M. A. The nuclear receptor corepressor deacetylase activating domain is essential for repression by thyroid hormone receptor. Mol. Endocrinol. 19, 1443–1451 (2005) source
The Discussion reports that the DAD is required for N-CoR to interact with HDAC3 in cells and is essential for repression by the thyroid hormone receptor (p. 1448). The paper does not address maintenance of normal circadian physiology, and its repression experiments concern the thyroid hormone receptor rather than other nuclear receptors. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [29] Yin, L. et al. Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways. Science 318, 1786–1789 (2007) source
May combine two claims.
Findingown dataAt salt concentrations higher than 50 mM, the HDAC3:SMRT-DAD complex dissociates and HDAC3 predominately takes the form of aggregate or oligomers.
“Interestingly at salt concentrations higher than 50mM the complex dissociated and the HDAC3 predominately took the form of aggregate or oligomers (Supplementary figure 2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDuring crystallisation, the HDAC3 tail is proteolysed but HDAC3 remains bound to SMRT-DAD and retains deacetylase activity.
“During crystallisation, the HDAC3 tail is proteolysed but HDAC3 remains bound to SMRT-DAD and retains deacetylase activity (Supplementary figure 3).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataHDAC3 and SMRT-DAD expressed in mammalian HEK293 cells form a tightly associated complex that remains associated during a three-step purification including size exclusion chromatography.
“The complex remained tightly associated during a three-step purification including size exclusion chromatography (Supplementary figure 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOn forming a complex with HDAC3, the amino terminal helix of the SMRT-DAD undergoes a major structural rearrangement from that seen in the NMR structure, no longer forms part of the core structure, and lies along the surface of HDAC3 making extensive intermolecular interactions.
“On forming a complex with HDAC3, the amino terminal helix of the DAD undergoes a major structural rearrangement, from that seen in the NMR structure, such that it no longer forms part of the core structure, but lies along the surface of HDAC3 making extensive intermolecular interactions (figure 1A & B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe remaining 3-helix bundle resembles a canonical SANT domain and buries a further 1,160 Å2 at the interface with HDAC3.
“The remaining 3-helix bundle resembles a canonical SANT domain and buries a further 1,160Å2 at the interface with HDAC3.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIns(1,4,5,6)P4 is sandwiched between HDAC3 and the DAD in a highly basic pocket, makes extensive contacts to both proteins, and buries a surface of 407 Å2.
“The Ins(1,4,5,6)P4 molecule is sandwiched between HDAC3 and the DAD, in a highly basic pocket, making extensive contacts to both proteins, burying a surface of 407Å2 (figure 2C and D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe residues that mediate interaction with Ins(1,4,5,6)P4 and the SANT domain from SMRT are conserved in both HDAC1 and HDAC2, but not in HDAC8.
“Significantly, the residues that mediate interaction with the Ins(1,4,5,6)P4 and the SANT domain from SMRT are conserved in both HDAC1 and 2, but not in HDAC8 (figure 3A), fitting with the observation that only HDAC8 is fully active in isolation.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe small molecule was identified as inositol tetraphosphate and assigned as D-myo-inositol-1,4,5,6-tetrakisphosphate based on the axial orientation of the hydroxyl group on carbon 2.
“The electron density was sufficiently well defined that the small molecule could be readily identified as inositol tetraphosphate. During further refinement it could be unambiguously assigned as D-myo-inositol-1,4,5,6-tetrakisphosphate (based on the axial orientation of the hydroxyl group on carbon 2)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn HDAC8, pseudo helix H1 has a regular stable helical structure, loop L1 is two amino acids shorter, and loop L6 contains a proline residue that partly orientates the loop away from the active site.
“In HDAC8 the pseudo helix H1 has a regular stable helical structure, loop L1 is two amino acids shorter and loop L6 contains a proline residue that partly orientates the loop away from the active site (figure 4D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAll designed mutations of Arg265 and loops L1 and L6 in HDAC3 co-expressed with SMRT-DAD resulted in total loss of deacetylase activity and abolished interaction with SMRT-DAD.
“Strikingly, all the designed mutations resulted not only in total loss of deacetylase activity (figure 5A) but also abolished interaction with the SMRT-DAD (figure 5B).”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningIn the reconstitution assay, HDAC activity was very sensitive to inositol phosphate concentration, and higher concentrations do not support reconstitution.
“HDAC activity was very sensitive to inositol phosphate concentration and higher concentrations do not support reconstitution.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA similar pattern of activation was seen using Ins(1,4,5)P3 and Ins(1,2,3,4,5,6)P6, but both required a 10-fold higher concentration to achieve a similar level of HDAC activity to that seen with Ins(1,4,5,6)P4.
“A similar pattern of activation was seen using both Ins(1,4,5)P3 and Ins(1,2,3,4,5,6)P6, but in both cases a 10-fold higher concentration was required to achieve a similar level of HDAC activity to that seen with Ins(1,4,5,6)P4.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThe tyrosine unique to HDAC3 might interact with substrate and possibly contribute to substrate specificity.
“This tyrosine is unique to HDAC3 and it seems that this residue might interact with substrate and possibly contribute to substrate specificity (Supplementary figure 4).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataModel building and refinement yielded an excellent map to 2.1 Å resolution with clear density for both HDAC3 and SMRT-DAD.
“Model building and refinement yielded an excellent map to 2.1Å resolution with clear density for both the HDAC3 and the SMRT-DAD (Supplementary figure 1).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningChanges in conformation and dynamics occur when the DAD and Ins(1,4,5,6)P4 bind HDAC3, and these facilitate substrate access to the active site resulting in enhanced enzyme activity.
“We propose that changes in both conformation and dynamics occur when the DAD and Ins(1,4,5,6)P4 bind to HDAC3 and that these facilitate substrate access to the active site resulting in enhanced enzyme activity.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningAssembly of the 3-way SMRT:HDAC3:Ins(1,4,5,6)P4 complex appears mutually interdependent, such that both SMRT-DAD and Ins(1,4,5,6)P4 are required for activation of HDAC3 enzymatic functionality.
“Consequently the assembly of the 3-way SMRT:HDAC3:Ins(1,4,5,6)P4 complex appears to be mutually interdependent, such that both the SMRT-DAD and the Ins(1,4,5,6)P4 are required for activation of the HDAC3 enzymatic functionality.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe requirement for Ins(1,4,5,6)P4 to enable complex formation may explain why recombinant proteins expressed in bacteria fail to interact, since bacteria probably do not contain sufficient Ins(1,4,5,6)P4 to support complex formation.
“The requirement for Ins(1,4,5,6)P4 to enable complex formation may contribute to the explanation as to why recombinant proteins expressed in bacteria fail to interact, since bacteria probably do not contain sufficient Ins(1,4,5,6)P4 to support complex formation.”
Quote in the paperNot a substantial claim- Rests on an assumption: Bacteria probably do not contain sufficient Ins(1,4,5,6)P4 to support formation of the SMRT:HDAC3 complex.
May combine two claims.
InterpretationreasoningLoop L6 seems very important for access to the active site, since Leu266 forms one wall of the active site tunnel and in the absence of Ins(1,4,5,6)P4 this loop is likely to be relatively mobile.
“This loop seems to be very important for access to the active site since Leu266 forms one wall of the active site tunnel and in the absence of the Ins(1,4,5,6)P4 this loop is likely to be relatively mobile.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningHigh levels of free inositol phosphate compete with complex formation, explaining why higher concentrations do not support reconstitution.
“This can be explained through high levels of free inositol phosphate competing with complex formation.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningAt physiological ionic strengths Ins(1,4,5,6)P4 is likely to dissociate readily and thus could regulate complex assembly.
“At physiological ionic strengths the Ins(1,4,5,6)P4 is likely to dissociate readily and thus could regulate complex assembly.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOdom et al. showed that Arg82 is an inositol phosphate kinase that converts Ins(1,4,5)P3 to Ins(1,4,5,6)P4 and that kinase activity is required for its role in transcriptional regulation.
“Odom et al showed that Arg82 is an inositol phosphate kinase that converts Ins(1,4,5)P3 to Ins(1,4,5,6)P4 and that kinase activity is required for its role in transcriptional regulation (figure 5d)36.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Odom, A. R. A role for nuclear inositol 1,4,5-trisphosphate kinase in transcriptional control. Science 287, 2026–2029 (2000) source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThere is some evidence that both PTEN and InsP4 levels change with progression through the cell cycle.
“However there is some evidence that both PTEN and InsP4 levels change with progression through the cell cycle45.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Mattingly, R. R., Stephens, L. R., Irvine, R. F. & Garrison, J. C. Effects of transformation with the v-src oncogene on inositol phosphate metabolism in rat-1 fibroblasts. D-myo-inositol 1,4,5,6-tetrakisphosphate is increased in v-src-transformed rat-1 fibroblasts and can be synthesized from D-myo-inositol 1,3,4-trisphosphate in cytosolic extracts. J. Biol. Chem. 266, 15144–15153 (1991) source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenYeast Arg82 is a transcriptional regulator of genes involved in arginine metabolism.
“Yeast Arg82 is a transcriptional regulator of genes involved in arginine metabolism.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationSeveral studies have previously implicated Ins(1,4,5,6)P4 as a regulator of gene expression and chromatin remodelling, although no molecular mechanism was identified.
“Importantly, several studies have previously implicated Ins(1,4,5,6)P4 as a regulator of gene expression and chromatin remodelling - although no molecular mechanism was identified.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningSequence conservation suggests that Ins(1,4,5,6)P4 plays a key role in corepressor assembly and activation of class I HDACs from yeast to man and is likely to act as a regulator of HDAC complex assembly.
“Sequence conservation suggests that Ins(1,4,5,6)P4 plays a key role in corepressor assembly and activation of class I HDACs from yeast to man and is likely to act as a regulator of HDAC complex assembly.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe final model has 97.8% residues in the favoured region, 2.0% in the allowed region and 0.2% in the outlier region of the Ramachandran plot.
“The final model has 97.8% residues in the favoured region, 2.0% in the allowed region and 0.2% in the outlier region of the Ramachandran plot.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Bacteria probably do not contain sufficient Ins(1,4,5,6)P4 to support formation of the SMRT:HDAC3 complex.
“since bacteria probably do not contain sufficient Ins(1,4,5,6)P4 to support complex formation.”
The paper relies on this without support.
The corepressor partners for HDAC1 and HDAC2, MTA(1-3) and CoREST(1-3), contain SANT domains analogous to the SMRT-DAD.
“Similarly, the corepressor partners for HDAC1 and 2, MTA(1-3) and CoREST(1-3), contain SANT domains that are analogous to the SMRT-DAD.”
The paper relies on this without support.
The key Ins(1,4,5,6)P4-binding residues are also found in the yeast HDAC Rpd3 and the Snt1 corepressor.
“given that the key residues are also found in the yeast HDAC, Rpd3, and the Snt1 corepressor”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In hHDAC1 and hHDAC3, the corresponding arginine is involved in inositol phosphate binding and is important for activity.
“In hHDAC1 and hHDAC3 this arginine is involved in inositol phosphate binding and is important for activity 38, 47, 48 .”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [48]
In “Mechanism of activation of HDAC3” (page unavailable), the paper identifies HDAC3 Arg265 as interacting with inositol tetraphosphate and reports that mutations targeting it abolished deacetylase activity. In “An essential role for Ins(1,4,5,6)P4” (page unavailable), it says the binding residues are conserved in HDAC1, but does not establish that the corresponding HDAC1 arginine binds inositol phosphate or is important for activity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLeu133 in a reported HDAC3 crystal structure would clash with the fluorophenyl group in the TNG260 HDAC2 structure.
“As depicted in the overlay in Fig. 2C, Leu133 in a reported HDAC3 crystal structure (PDB 4A69; ref. 32) would clash with the fluorophenyl group in the TNG260 HDAC2 structure (PDB 9NTB).”
From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [32]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Phosphate count conflicts with the listed positions
MinorThe name lists five phosphorylated positions but calls the product a tetraphosphate (P4). The next product lists the same five positions and calls it a pentaphosphate (P5).
“Ins(1,3,4,5,6)P4”
“Ins(1,3,4,5,6)P5”
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“It is also possible that changing levels of Ins(1,4,5,6)P 4 may contribute to the circadian regulation of HDAC3 activit”
BackgroundBoth corepressor proteins SMRT and N‐CoR exist in large protein complexes containing HDAC3
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“Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P4, which may act as a regulator—potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators.”
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BackgroundThe histone deacetylase-3 complex contains nuclear receptor corepressors
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BackgroundModulation of ATP-Dependent Chromatin-Remodeling Complexes by Inositol Polyphosphates
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“Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P4, which may act as a regulator—potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators.”
BackgroundInfluentialA core–BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes
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Corepressors selectively control the transcriptional activity of PPARγ in adipocytesPreprint
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SMRT Derepression by the IκB Kinase α
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“1 ) diffracted to 2 A and the structure was solved by molecular replacement with an HDAC8 structur”
MethodHistone deacetylases—an important class of cellular regulators with a variety of functions
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“Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P4, which may act as a regulator—potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators.”
BackgroundInfluentialStructural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery
Oberoi, J., Fairall, L., Watson, P. J., Yang, J.-C., Czimmerer, Z., Kampmann, T., Goult, B. T., Greenwood, J. A., Gooch, J. T., Kallenberger, B. C., et al. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1983 · Cited by 165 · see citing works
Self-citationNegative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A
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“HDAC3 and the SMRT-DAD each contribute five hydrogen bonds and salt bridges to the Ins(1,4,5,6)P4 (His17, Gly21, Lys25, Arg265 & Arg301 and Lys449, Tyr470, Tyr471, Lys474 & Lys 475 respectively) (figure 2E).”
BackgroundInfluentialAssembly of the SMRT–histone deacetylase 3 repression complex requires the TCP-1 ring complex
Guenther, M. G., Yu, J., Kao, G. D., Yen, T. J., & Lazar, M. A. (2002) · Genes & Development · doi:10.1101/gad.1037502 · Cited by 138 · cited 1× · see citing works
“It has been proposed that the assembly of the HDAC3 and SMRT-DAD requires a chaperone complex, because when these proteins are expressed in bacteria they do not form a comple”
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“We have previously reported the structure of the isolated DAD from SMR”
MethodSelf-citationNALASKOWSKI, M. M., DESCHERMEIER, C., FANICK, W., & MAYR, G. W. (2002) · Biochemical Journal · doi:10.1042/bj20020327 · Cited by 89 · see citing works
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Molecular cloning and expression of a rat hepatic multiple inositol polyphosphate phosphatase
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“The most likely enzyme is the well-known tumour suppressor gene PTE”
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“Recruitment of HDAC3 to the DAD is essential for repression by certain nuclear receptors and for the maintenance of normal circadian physiolog”
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“The most likely enzyme is the well-known tumour suppressor gene PTE”
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Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials
Cheng, Y., He, C., Wang, M., Ma, X., Mo, F., Yang, S., Han, J., & Wei, X. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0095-0 · Cited by 1,097 · see citing works
“NCoR also interacts with HDAC1, HDAC2 and the class II deacetylases HDAC4, HDAC5, and HDAC7, but usually not in the form of a complex.(221,222) Deleted in breast cancer 1 (DBC1) and active regulator of SIRT1 (AROS) are two proteins that are able to bind to SIRT1, whereas their interactions present opposite functions.”
BackgroundClass I histone deacetylases (HDAC1–3) are histone lysine delactylases
Moreno-Yruela, C., Zhang, D., Wei, W., Bæk, M., Liu, W., Gao, J., Danková, D., Nielsen, A. L., Bolding, J. E., Yang, L., et al. (2022) · Science Advances · doi:10.1126/sciadv.abi6696 · Cited by 841 · see citing works
A short guide to histone deacetylases including recent progress on class II enzymes
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Modulators of Protein–Protein Interactions
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Class I HDACs Share a Common Mechanism of Regulation by Inositol Phosphates
Millard, C. J., Watson, P. J., Celardo, I., Gordiyenko, Y., Cowley, S. M., Robinson, C. V., Fairall, L., & Schwabe, J. W. R. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.05.020 · Cited by 396 · see citing works
“The Role of Inositol Phosphate in HDAC1 and HDAC3 Corepressor Complexes Wepreviously demonstrated that Ins(1,4,5,6)P4, which copurified with the complex from mammalian cells, was essential for the interaction between HDAC3 and the extended SANT domain from the SMRT corepressor (Watson et al., 2012).”
BackgroundMethodInfluentialSelf-citationLysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics
Ali, I., Conrad, R. J., Verdin, E. M., & Ott, M. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00181 · Cited by 366 · see citing works
The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy
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“Inositol phosphate, an intermolecular “glue”; binds to the interface between the co-repressors and HDAC catalytic domains, improving the catalytic activity of the HDACs in NuRD and NCoR/SMRT complexes (Watson et al., 2012, 2016; Millard et al., 2013).”
BackgroundKelly, R. D. W., & Cowley, S. M. (2013) · Biochemical Society Transactions · doi:10.1042/bst20130010 · Cited by 297 · see citing works
Emerging roles of the corepressors NCoR1 and SMRT in homeostasis
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“For a more detailed discussion of how NCoR1/SMRT mechanistically regulate transcription, we refer the interested reader to some recent reviews (Perissi et al. 2010; Watson et al. 2012b).”
BackgroundInfluentialSun, Z., Feng, D., Fang, B., Mullican, S. E., You, S.-H., Lim, H., Everett, L. J., Nabel, C. S., Li, Y., Selvakumaran, V., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.10.022 · Cited by 247 · see citing works
“…Tyr residue (Y298 in HDAC3) is located within the active site and is catalytically essential in stabilizing the tetrahedral intermediate and polarizing the substrate carbonyl for nucleophilic attack in coordination with Zn ion (Figures 2A and S2; Lombardi et al., 2011; Watson et al., 2012).”
BackgroundInfluentialMicrobiota-derived metabolite promotes HDAC3 activity in the gut
Wu, S.-E., Hashimoto‐Hill, S., Woo, V., Eshleman, E. M., Whitt, J., Engleman, L., Karns, R. A., Denson, L. A., Haslam, D. B., & Alenghat, T. (2020) · Nature · doi:10.1038/s41586-020-2604-2 · Cited by 253 · see citing works
Structure and function insights into the NuRD chromatin remodeling complex
Torchy, M., Hamiche, A., & Klaholz, B. P. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1880-8 · Cited by 244 · see citing works
“This observation had been made previously on a HDAC3-SMRT complex, copurified from mammalian cells with endogenous Ins[1, 4, 5, 6]P4 while direct complex formation from the individually purified proteins failed [76].”
BackgroundInsights into the activation mechanism of class I HDAC complexes by inositol phosphates
Watson, P. J., Millard, C. J., Riley, A. M., Robertson, N. S., Wright, L. C., Godage, H. Y., Cowley, S. M., Jamieson, A. G., Potter, B. V. L., & Schwabe, J. W. R. (2016) · Nature Communications · doi:10.1038/ncomms11262 · Cited by 244 · see citing works
Self-citationEngineering enzyme access tunnels
Kokkonen, P., Bednář, D., Pinto, G., et al. (2019) · Biotechnology Advances · doi:10.1016/j.biotechadv.2019.04.008 · Cited by 237 · see citing works
Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors
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Self-citationIntegrative regulation of physiology by histone deacetylase 3
Emmett, M. J., & Lazar, M. A. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0076-0 · Cited by 202 · see citing works
Beyond histone acetylation—writing and erasing histone acylations
Zhao, S., Zhang, X., & Li, H. (2018) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2018.10.001 · Cited by 207 · see citing works
Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo
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Histone deacetylases: structural determinants of inhibitor selectivity
Micelli, C., & Rastelli, G. (2015) · Drug Discovery Today · doi:10.1016/j.drudis.2015.01.007 · Cited by 196 · see citing works
The nucleosome remodeling and deacetylase complex in development and disease
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“A similar paradigm has been proposed for all class I HDACs and their association with SANT domains in the context of different co-repressor complexes, such as the HDAC3- containing SMRT co-repressor complex [41].”
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Targeting Class I Histone Deacetylases in a “Complex” Environment
Millard, C. J., Watson, P. J., Fairall, L., & Schwabe, J. W. R. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.12.006 · Cited by 180 · see citing works
Self-citationMarek, M., Kannan, S., Hauser, A.-T., Moraes Mourão, M., Caby, S., Cura, V., Stolfa, D. A., Schmidtkunz, K., Lancelot, J., Andrade, L., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003645 · Cited by 173 · see citing works
Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors
Porter, N. J., Mahendran, A., Breslow, R., & Christianson, D. W. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718823114 · Cited by 190 · see citing works
POWERDRESS interacts with HISTONE DEACETYLASE 9 to promote aging in Arabidopsis
Chen, X., Lü, L., Mayer, K. S., Scalf, M., Qian, S., Lomax, A., Smith, L. M., & Zhong, X. (2016) · eLife · doi:10.7554/elife.17214 · Cited by 175 · see citing works
“SMRT/N-CoR has an additional function in stimulating HDAC3 deacetylase activity in vitro (Guenther et al., 2001; Watson et al., 2012).”
BackgroundMLKL Requires the Inositol Phosphate Code to Execute Necroptosis
Dovey, C. M., Diep, J., Clarke, B. P., Hale, A. T., McNamara, D. E., Guo, H., Brown, N. W., Cao, J. Y., Grace, C. R., Gough, P. J., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.05.010 · Cited by 175 · see citing works
Role of Inositols and Inositol Phosphates in Energy Metabolism
Chatree, S., Thongmaen, N., Tantivejkul, K., Sitticharoon, C., & Vučenik, I. (2020) · Molecules · doi:10.3390/molecules25215079 · Cited by 168 · see citing works
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“Although it was previously thought that HDAC complexes are constitutively active, it was recently shown that the deacetylase activity of HDAC1 and HDAC3 is regulated through binding of an IP4 molecule sandwiched between the HDAC and its cognate corepressor (5, 43).”
BackgroundSelf-citationHistone Deacetylases in Bone Development and Skeletal Disorders
Bradley, E. W., Shull, L. C., van Wijnen, A. J., McGee‐Lawrence, M. E., & Westendorf, J. J. (2015) · Physiological Reviews · doi:10.1152/physrev.00004.2015 · Cited by 163 · see citing works
Dichotomous engagement of HDAC3 activity governs inflammatory responses
Nguyen, H. C. B., Adlanmerini, M., Hauck, A. K., & Lazar, M. A. (2020) · Nature · doi:10.1038/s41586-020-2576-2 · Cited by 150 · see citing works
Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding
Chen, S., Jiao, L., Shubbar, M., Yang, X., & Liu, X. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.01.039 · Cited by 154 · see citing works
“Indeed, phospholipids and lipid headgroups are known to modulate the enzymatic activity and chromatin association of certain histone modifying and chromatin remodeling complexes (Hamann and Blind, 2018; Kutateladze, 2012; Watson et al., 2012).”
BackgroundChemical genomics reveals histone deacetylases are required for core regulatory transcription
Gryder, B. E., Wu, L., Woldemichael, G. M., Pomella, S., Quinn, T. R., Park, P. M. C., Cleveland, A. H., Stanton, B. Z., Song, Y., Rota, R., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11046-7 · Cited by 143 · see citing works
Structure, mechanism, and inhibition of the zinc-dependent histone deacetylases
Porter, N. J., & Christianson, D. W. (2019) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2019.01.004 · Cited by 146 · see citing works
Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor
Escoter-Torres, L., Caratti, G., Mechtidou, A., Tuckermann, J. P., Uhlenhaut, N. H., & Vettorazzi, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01859 · Cited by 146 · see citing works
“This occurs by recruitment of a GR-NCOR1HDAC3 complex to an nGRE in exon 6 of the NR3C1 gene (44).”
BackgroundInfluentialKuo, H., Chang, T., Chiang, S., Wang, W., Charng, Y., & Chiou, T. (2014) · The Plant Journal · doi:10.1111/tpj.12650 · Cited by 138 · see citing works
Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space
Kim, Y. H., & Lazar, M. A. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa014 · Cited by 146 · see citing works
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“The nucleosome remodelling and deacetylase (NuRD) complex is one of at least five corepressor complexes that recruits and activates class I histone deacetylase (HDACs) enzymes and directs their activity to chromatin (Bantscheff et al., 2011; Guenther et al., 2000; Humphrey et al., 2001; Itoh et al., 2015; Kelly and Co…”
BackgroundMethodSelf-citationMechanism of Crosstalk between the LSD1 Demethylase and HDAC1 Deacetylase in the CoREST Complex
Song, Y., Dagil, L., Fairall, L., Robertson, N., Wu, M., Ragan, T. J., Savva, C. G., Saleh, A., Morone, N., Kunze, M. B. A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.091 · Cited by 141 · see citing works
Self-citationKelly, R. D. W., Chandru, A., Watson, P. J., Song, Y., Blades, M., Robertson, N. S., Jamieson, A. G., Schwabe, J. W. R., & Cowley, S. M. (2018) · Scientific Reports · doi:10.1038/s41598-018-32927-9 · Cited by 138 · see citing works
Self-citationNext-generation of selective histone deacetylase inhibitors
Yang, F., Zhao, N., Ge, D., & Chen, Y. (2019) · RSC Advances · doi:10.1039/c9ra02985k · Cited by 144 · see citing works
Wilson, M., Jessen, H. J., & Saiardi, A. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007848 · Cited by 120 · see citing works
“Notably, inositol phosphates have been found in crystals of proteins purified from eukaryotic cells (mammalian, insect, and yeast), without addition of exogenous inositol phosphates (33, 35, 39); these endogenously-derived ligands were also not associated with cations.”
Molecular basis for hierarchical histone de-β-hydroxybutyrylation by SIRT3
Zhang, X., Cao, R., Niu, J., Yang, S., Ma, H., Zhao, S., & Li, H. (2019) · Cell Discovery · doi:10.1038/s41421-019-0103-0 · Cited by 124 · see citing works
Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate
Wang, Q., Vogan, E. M., Nocka, L. M., Rosen, C. E., Zorn, J. A., Harrison, S. C., & Kuriyan, J. (2015) · eLife · doi:10.7554/elife.06074 · Cited by 122 · see citing works
“The activation of Class I Histone Deacetylases (HDACs) requires the formation of a multi-subunit co-repressor complex, in which Ins(1,4,5,6)P4 serves as an intermolecular glue that cements the complex together (Watson et al., 2012;Millard et al., 2013).”
BackgroundMarek, M., Shaik, T. B., Heimburg, T., Chakrabarti, A., Lancelot, J., Ramos-Morales, E., Da Veiga, C., Kalinin, D., Melesina, J., Robaa, D., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01087 · Cited by 123 · see citing works
Histone deacetylase 3 (HDAC3) inhibitors as anticancer agents: A review
Sarkar, R., Banerjee, S., Amin, S. A., Adhikari, N., & Jha, T. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112171 · Cited by 121 · see citing works
Sei, Y., Zhao, X., Forbes, J., Szymczak, S., Li, Q., Trivedi, A., Voellinger, M., Joy, G., Feng, J., Whatley, M., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.008 · Cited by 119 · see citing works
Characterization of Fully Recombinant Human 20S and 20S-PA200 Proteasome Complexes
Rêgo, A. T., & da Fonseca, P. C. A. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.014 · Cited by 118 · see citing works
Discovery of histone deacetylase 3 (HDAC3)-specific PROTACs
Xiao, Y., Wang, J., Zhao, L., Chen, X., Zheng, G., Zhang, X., & Liao, D. (2020) · Chemical Communications · doi:10.1039/d0cc03243c · Cited by 130 · see citing works
Rajendran, P., Kidane, A. I., Yu, T., Dashwood, W., Bisson, W. H., Löhr, C. V., Ho, E., Williams, D. E., & Dashwood, R. H. (2013) · Epigenetics · doi:10.4161/epi.24710 · Cited by 119 · see citing works
Shears, S. B. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.26017 · Cited by 112 · see citing works
“Initial studies (Watson et al., 2012) focused on the active ligand as being Ins(1,4,5,6) P4, but later work (Watson et al., 2016) showed that a similar degree of HDAC activation could be elicited by either 5-PP-InsP4 or by a 1- phosphonoacetate analogue of 1-InsP7.”
BackgroundStrategies To Design Selective Histone Deacetylase Inhibitors
Melesina, J., Simoben, C. V., Praetorius, L., Bülbül, E. F., Robaa, D., & Sippl, W. (2021) · ChemMedChem · doi:10.1002/cmdc.202000934 · Cited by 118 · see citing works
Blind, R. D., Suzawa, M., & Ingraham, H. A. (2012) · Science Signaling · doi:10.1126/scisignal.2003111 · Cited by 117 · see citing works
“This would be similar to the bridging function that inositol tetraphosphates appear to serve in co-repressor complex assembly (38).”
BackgroundPorter, N. J., Osko, J. D., Diedrich, D., Kurz, T., Hooker, J. M., Hansen, F. K., & Christianson, D. W. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01013 · Cited by 111 · see citing works
Transcriptional Coregulators: Fine-Tuning Metabolism
Mouchiroud, L., Eichner, L. J., Shaw, R. J., & Auwerx, J. H. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.027 · Cited by 111 · see citing works
“Together with inositol polyphosphate multikinase (IPMK), the phosphatase and tensin homolog (PTEN) leads to the formation of Ins(1,4,5,6)P4, which acts as an adhesive molecule for the SMRT/HDAC3 complex, enhancing the repressive activity of these corepressors (Watson et al., 2012).”
BackgroundInfluentialTurnbull, R. E., Fairall, L., Saleh, A., Kelsall, E., Morris, K. L., Ragan, T. J., Savva, C. G., Chandru, A., Millard, C. J., Makarova, O. V., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17078-8 · Cited by 108 · see citing works
Self-citationde la Vega, L., Grishina, I., Moreno, R., Krüger, M., Braun, T. W., & Schmitz, M. L. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.03.003 · Cited by 106 · see citing works
“Another group I member is HDAC3, which contributes to several fundamental processes including the control of cardiac energy metabolism and regulation of S phase progression and DNA damage control (Watson et al., 2012).”
BackgroundFOXP3+ regulatory T cell development and function require histone/protein deacetylase 3
Wang, L., Liu, Y., Han, R., Beier, U. H., Bhatti, T. R., Akimova, T., Greene, M. I., Hiebert, S. W., & Hancock, W. W. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77088 · Cited by 103 · see citing works
“IP4 helps stabilize this interaction and also triggers a conformational change in HDAC3 that makes its catalytic site more accessible to substrate (26, 27).”
An evolving understanding of nuclear receptor coregulator proteins
Millard, C. J., Watson, P. J., Fairall, L., & Schwabe, J. W. R. (2013) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0227 · Cited by 101 · see citing works
Self-citationHDAC-targeting epigenetic modulators for cancer immunotherapy
Cheng, B., Pan, W., Xiao, Y., Ding, Z., Zhou, Y., Fei, X., Liu, J., Su, Z., Peng, X., & Chen, J. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116129 · Cited by 112 · see citing works
Chemical and structural biology of protein lysine deacetylases
Yoshida, M., Kudo, N., Kosono, S., & Ito, A. (2017) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.93.019 · Cited by 102 · see citing works
Suzuki, T., Kasuya, Y., Itoh, Y., Ota, Y., Zhan, P., Asamitsu, K., Nakagawa, H., Okamoto, T., & Miyata, N. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068669 · Cited by 104 · see citing works
“Azides Az1– Az14 bearing an aromatic ring were expected to interact with aromatic amino acid residues such as Tyr and Phe which form the HDAC3 active pocket [36].”
BackgroundMethodEmerging targetome and signalome landscape of gut microbial metabolites
Zheng, X., Cai, X., & Hao, H. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2021.12.011 · Cited by 100 · see citing works
Transcription and beyond: the role of mammalian class I lysine deacetylases
Moser, M. A., Hagelkrüys, A., & Seiser, C. (2013) · Chromosoma · doi:10.1007/s00412-013-0441-x · Cited by 96 · see citing works
“Interestingly, it was shown recently that inositol-tetraphosphate (IP4) positively affects class I KDAC co-repressor complex formation and activity (Millard et al. 2013; Watson et al. 2012).”
BackgroundInositol polyphosphates intersect with signaling and metabolic networks via two distinct mechanisms
Wu, M., Chong, L. S., Perlman, D. H., Resnick, A. C., & Fiedler, D. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1606853113 · Cited by 91 · see citing works
Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases
Wagner, F. F., Weïwer, M., Lewis, M. C., & Holson, E. B. (2013) · Neurotherapeutics · doi:10.1007/s13311-013-0226-1 · Cited by 99 · see citing works
“[44] has elucidated the interactions of HDACs 1 and 3 with their corresponding corepressor complexes in association with inositol tetraphosphate.”
BackgroundThe signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1
Blind, R. D., Sablin, E. P., Kuchenbecker, K. M., Chiu, H., Deacon, A. M., Das, D., Fletterick, R. J., & Ingraham, H. A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1416740111 · Cited by 96 · see citing works
“This mechanism is analogous to the bridging functions of soluble inositols (28) or to membrane-bound PIP3 in mediating protein–lipid interactions at the plasma membrane.”
BackgroundThaler, F., & Mercurio, C. (2013) · ChemMedChem · doi:10.1002/cmdc.201300413 · Cited by 95 · see citing works
Mutations in <i>TBL1X</i> Are Associated With Central Hypothyroidism
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“In addition, we used frozen hypothala- mus and pituitary glands from two patients for Western blot analysis (see Supplemental Material).”
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- Authors
- Watson, P. J., Fairall, L., Santos, G. M., & Schwabe, J. W. R.
- Affiliations
- University of Leicester (GB)
- Corresponding author
- Schwabe, John W. R.
- Venue
- Nature
- Published
- 2012-01
- Volume
- 481
- Issue
- 7381
- Pages
- 335-340
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3272448
- OpenAlex
- W1973577140
- Cited by
- 505
- References
- 51
- Citations by year
- 2026: 34 · 2025: 45 · 2024: 35 · 2023: 39 · 2022: 29 · 2021: 30 · 2020: 41 · 2019: 46 · 2018: 33 · 2017: 27 · 2016: 19 · 2015: 40 · 2014: 29 · 2013: 39 · 2012: 19
- FWCI
- 16.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- Wellcome Trust (100237, WT085408, 085408)
- Division of Materials Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- HDAC3, NCOR2, inositol tetrakisphosphate, histone deacetylase, corepressor complex, protein complex structure, structural rearrangement, inositol phosphate signaling, transcriptional regulation, cancer drug targets
- MeSH terms
- Histone Deacetylase 3, Amino Acid Sequence, Enzyme Activation, Histone Deacetylases, Humans, Inositol Phosphates, Models, Molecular, Molecular Sequence Data, Structure-Activity Relationship, Conserved Sequence, Protein Structure, Tertiary, Crystallography, X-Ray, Multiprotein Complexes, Protein Multimerization, Nuclear Receptor Co-Repressor 2, Molecular Targeted Therapy
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