The DOI matches its Crossref record; 50 of the 51 references it cites were found in a registry or an index; 25 of the 36 sources its claims cite were checked for support.
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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29 Own result · 19 Own interpretation · 7 Partly supported · 4 No basis given · 3 Own method · 2 Supported · 2 Supported so far · 2 Not supported · 2 No full text of the sources · 1 Not checked yet · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“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)”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > An essential role for Ins(1,4,5,6)P4
What the sources say
- Disputedcites [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) sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
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plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Disputed
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In the paper
“HDACs 1, 2 and 3 require association with large multisubunit corepressor complexes for maximal activity7-12.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Abstract
What the sources say
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [12] Wen, Y. D. et al. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 97, 7202–7207 (2000) sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Along with a further extended region, this DAD-specific motif buries a surface of 1,178Å2.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Structural rearrangement of the SMRT-DAD
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The active site lies at the base of a tunnel leading from the surface of the protein.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Overall architecture of the complex
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This region differs between HDAC8 and HDAC3.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Structural rearrangement of the SMRT-DAD
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Overall architecture of the complex
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Structural rearrangement of the SMRT-DAD
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Indeed, in HDAC3, helix H1 is distorted and can only be considered to be a pseudo-helix.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Structural rearrangement of the SMRT-DAD
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > An essential role for Ins(1,4,5,6)P4
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Mechanism of activation of HDAC3
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 31
- Probably not a substantial claim. 11
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“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).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
What the sources say
- Disputedcites [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) sourceExperimental — accuracy not yet measured
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.
- Not checked — no full text of the sourcecites [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
- Could not verifycites [44] Di Cristofano, A. & Pandolfi, P. P. The multiple roles of PTEN in tumor suppression. Cell 100, 387–390 (2000) sourceExperimental — accuracy not yet measured
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)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Overall architecture of the complex
What the sources say
- Supportedcites [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
The citation is attached to HDAC8, not HDAC2. The Introduction identifies this work as presenting HDAC8 crystal structures, and the Results and Discussion describe HDAC8 as having an eight-stranded parallel β sheet between α helices. The paper does not need to establish the citing authors’ comparison with their HDAC3 structure. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
What the sources say
- Partly supportedcites [37] Steger, D. J. Regulation of chromatin remodeling by inositol polyphosphates. Science 299, 114–116 (2003) sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
What the sources say
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Abstract
What the sources say
- Supportedcites [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 Discussion (page unavailable) states that the SMRT DAD contains SANT1 and requires 37 amino acids immediately N-terminal to it. The Results (page unavailable) report that deletion of the region immediately N-terminal to SANT1 prevents HDAC3 activation and endogenous HDAC3 coimmunoprecipitation; the paper also describes that region as required for binding and activation. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Of these, only HDAC8 is a fully functional enzyme in isolation5,6.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Abstract
What the sources say
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
The Results state that, unlike other class I HDACs, HDAC8 does not require protein cofactors for activity in vitro. They also report that purified HDAC8 deacetylated core histones, supporting the claim that it functions in isolation. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Abstract
What the sources say
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [12] Wen, Y. D. et al. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 97, 7202–7207 (2000) sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The DAD both recruits and activates HDAC310-12.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Abstract
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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 describe the SMRT DAD as binding HDAC3 and activating its enzyme activity (Fig. 6). They also report that a DAD-containing SMRT fragment formed a tightly associated, enzymatically active complex with HDAC3 (Fig. 8), supporting both recruitment and activation. (LLM, conf=0.92)
- Supportedcites [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 Results report that the N-CoR fragment spanning residues 267–549 binds HDAC3. The section “N-CoR Augments HDAC3 activity” reports that this same fragment significantly increases HDAC3 deacetylase activity. The paper does not use the term DAD, but it supports the attributed binding-and-activation function. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Abstract
What the sources say
- Supportedcites [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 — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Abstract
What the sources say
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
hedged- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Recruitment of HDAC3 to the DAD is essential for repression by certain nuclear receptors and for the maintenance of normal circadian physiology27-29.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Abstract
What the sources say
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [29] Yin, L. et al. Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways. Science 318, 1786–1789 (2007) source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly at salt concentrations higher than 50mM the complex dissociated and the HDAC3 predominately took the form of aggregate or oligomers (Supplementary figure 2).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Overall architecture of the complex
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“During crystallisation, the HDAC3 tail is proteolysed but HDAC3 remains bound to SMRT-DAD and retains deacetylase activity (Supplementary figure 3).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Overall architecture of the complex
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The complex remained tightly associated during a three-step purification including size exclusion chromatography (Supplementary figure 1).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Overall architecture of the complex
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Structural rearrangement of the SMRT-DAD
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The remaining 3-helix bundle resembles a canonical SANT domain and buries a further 1,160Å2 at the interface with HDAC3.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Structural rearrangement of the SMRT-DAD
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > An essential role for Ins(1,4,5,6)P4
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > An essential role for Ins(1,4,5,6)P4
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > An essential role for Ins(1,4,5,6)P4
boosted- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Mechanism of activation of HDAC3
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Mechanism of activation of HDAC3
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“HDAC activity was very sensitive to inositol phosphate concentration and higher concentrations do not support reconstitution.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Mechanism of activation of HDAC3
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Mechanism of activation of HDAC3
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Overall architecture of the complex
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Overall architecture of the complex
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Mechanism of activation of HDAC3
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > An essential role for Ins(1,4,5,6)P4
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > An essential role for Ins(1,4,5,6)P4
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Bacteria probably do not contain sufficient Ins(1,4,5,6)P4 to support formation of the SMRT:HDAC3 complex.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Mechanism of activation of HDAC3
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This can be explained through high levels of free inositol phosphate competing with complex formation.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Mechanism of activation of HDAC3
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At physiological ionic strengths the Ins(1,4,5,6)P4 is likely to dissociate readily and thus could regulate complex assembly.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
What the sources say
- Not checked — no full text of the sourcecites [36] Odom, A. R. A role for nuclear inositol 1,4,5-trisphosphate kinase in transcriptional control. Science 287, 2026–2029 (2000) source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“However there is some evidence that both PTEN and InsP4 levels change with progression through the cell cycle45.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
What the sources say
- Not checked — no full text of the sourcecites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Yeast Arg82 is a transcriptional regulator of genes involved in arginine metabolism.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Methods > Structure determination
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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 STK11 -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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
“Ins(1,3,4,5,6)P4”
§ Structure of HDAC3 bound to corepressor and inositol tetraphosphate > Does Ins(1,4,5,6)P4 regulate HDACs?
“Ins(1,3,4,5,6)P5”
Citations
Cites
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 29,915
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,317
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463
Lysine acetylation targets protein complexes and co-regulates major cellular functions
Choudhary, C., Kumar, C., Gnad, F., Nielsen, M. L., Rehman, M., Walther, T. C., Olsen, J. V., & Mann, M. (2009) · Science · doi:10.1126/science.1175371 · Cited by 4,040 · cited 6×
“Similarly, the co-repressor partners for HDAC1 and 2 (that is, MTA1, 2 and 3 and CoREST1, 2 and 3) contain SANT domains that are analogous to SMRT-DAD.”
BackgroundMethodResultInfluentialHistone acetylation and transcriptional regulatory mechanisms
Struhl, K. (1998) · Genes & Development · doi:10.1101/gad.12.5.599 · Cited by 1,815 · cited 3×
“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 tenfold higher concentration was required to achieve a similar level of HDAC activity to that seen with Ins(1,4,5,6)P4.”
MethodResultInfluentialMétivier, R., Penot, G., Hübner, M. R., Reid, G., Brand, H., Koš, M., & Gannon, F. (2003) · Cell · doi:10.1016/s0092-8674(03)00934-6 · Cited by 1,431
A complex containing N-CoR, mSln3 and histone deacetylase mediates transcriptional repression
Heinzel, T., Lavinsky, R. M., Mullen, T.-M., Söderström, M., Laherty, C. D., Torchia, J., Yang, W., Brard, G., Ngo, S. D., Davie, J., et al. (1997) · Nature · doi:10.1038/387043a0 · Cited by 1,210
Marks, P. A., & Breslow, R. (2007) · Nature Biotechnology · doi:10.1038/nbt1272 · Cited by 1,198
The Multiple Roles of PTEN in Tumor Suppression
Di Cristofano, A., & Pandolfi, P. P. (2000) · Cell · doi:10.1016/s0092-8674(00)80674-1 · Cited by 1,182
Cited by
Sorted by citations
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
“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
A short guide to histone deacetylases including recent progress on class II enzymes
Park, S.-Y., & Kim, J. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0382-4 · Cited by 547
Modulators of Protein–Protein Interactions
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C. (2014) · Chemical Reviews · doi:10.1021/cr400698c · Cited by 497
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
“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 375
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
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 251
“…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 255
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 253
“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
Self-citationEngineering enzyme access tunnels
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Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors
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Self-citationIntegrative regulation of physiology by histone deacetylase 3
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Beyond histone acetylation—writing and erasing histone acylations
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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
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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
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Self-citationUnusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors
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POWERDRESS interacts with HISTONE DEACETYLASE 9 to promote aging in Arabidopsis
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“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
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Role of Inositols and Inositol Phosphates in Energy Metabolism
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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
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Dichotomous engagement of HDAC3 activity governs inflammatory responses
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Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding
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“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
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Structure, mechanism, and inhibition of the zinc-dependent histone deacetylases
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Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor
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“This occurs by recruitment of a GR-NCOR1HDAC3 complex to an nGRE in exon 6 of the NR3C1 gene (44).”
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Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space
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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
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Self-citationNext-generation of selective histone deacetylase inhibitors
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“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
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Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate
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“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).”
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Histone deacetylase 3 (HDAC3) inhibitors as anticancer agents: A review
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Characterization of Fully Recombinant Human 20S and 20S-PA200 Proteasome Complexes
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Discovery of histone deacetylase 3 (HDAC3)-specific PROTACs
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“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
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“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
Transcriptional Coregulators: Fine-Tuning Metabolism
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“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
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“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 107
“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 111
Self-citationHDAC-targeting epigenetic modulators for cancer immunotherapy
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Chemical and structural biology of protein lysine deacetylases
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“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
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Transcription and beyond: the role of mammalian class I lysine deacetylases
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“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 92
Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases
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“[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 99
“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.”
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Mutations in TBL1X Are Associated With Central Hypothyroidism
Heinen, C. A., Losekoot, M., Sun, Y., Watson, P. J., Fairall, L., Joustra, S. D., Zwaveling-Soonawala, N., Oostdijk, W., van den Akker, E. L. T., Alders, M., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-2531 · Cited by 92
“In addition, we used frozen hypothala- mus and pituitary glands from two patients for Western blot analysis (see Supplemental Material).”
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“Inositol phosphates regulate HDAC3 [66].”
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Comprehensive review of histone lactylation: Structure, function, and therapeutic targets
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Readers of DNA methylation, the MBD family as potential therapeutic targets
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Biosynthesis and possible functions of inositol pyrophosphates in plants
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“This HDAC activity is dependent on InsP4, which is known to act as a “molecular glue” allowing the HDAC Rpd3L complex to interact with its co-repressor, SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) (Watson et al., 2012).”
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“It is known that the GR DNA binding domain (DBD) interacts with (+)GRE and IR nGRE sequences (18, 19), and that deletion of the GR DBD (ΔDBD) or either one of the two zinc fingers (ΔZF1/ ΔZF2) abolished these interactions (Fig.”
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“…(1) sequence alignment shows that the residues that mediate the HDAC3-IP4 interaction are conserved across the class I HDACs, including in Rpd3 (Watson et al., 2012), and (2) examination of the HDAC3-SMRT structure (Protein Data Bank ID code 4A69) shows that approximately half of the IP4 ring…”
InfluentialNuclear phosphoinositides and their impact on nuclear functions
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“Ipk2 deletion reduces levels of IP4, which can act as a transcriptional regulator (Watson et al., 2012), and IP6, which can regulate the activity of DEAD box protein Dbp5 in a Gle1-dependent manner at the cytoplasmic face of the nuclear pore complex during mRNA export (Alcázar-Román et al., 2010).”
BackgroundHDAC3 maintains oocyte meiosis arrest by repressing amphiregulin expression before the LH surge
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Nuclear receptor corepressor complexes in cancer: mechanism, function and regulation.
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“, an inositol tetraphosphate molecule, which acts as an “intermolecular glue” between the two protein partners and contributes to the activation of HDAC3 (71).”
BackgroundStructure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK
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“syringae, as well as the presence of IP4 in the histone deacetylase HDAC3-SMART/DAD complex (Watson et al., 2012).”
BackgroundAuto‐regulated Protein Assembly on a Supramolecular Scaffold
Rennie, M. L., Fox, G. C., Pérez, J., & Crowley, P. B. (2018) · Angewandte Chemie International Edition · doi:10.1002/anie.201807490 · Cited by 75
Diverse nucleosome Site-Selectivity among histone deacetylase complexes
Wang, Z. A., Millard, C. J., Lin, C., Gurnett, J. E., Wu, M., Lee, K., Fairall, L., Schwabe, J. W. R., & Cole, P. A. (2020) · eLife · doi:10.7554/elife.57663 · Cited by 72
Self-citationNADPH levels affect cellular epigenetic state by inhibiting HDAC3–Ncor complex
Li, W., Kou, J., Qin, J., Li, L., Zhang, Z., Pan, Y., Xue, Y., & Du, W. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00330-2 · Cited by 79
Switching between humoral and cellular immune responses in Drosophila is guided by the cytokine GBP
Tsuzuki, S., Matsumoto, H., Furihata, S., et al. (2014) · Nature Communications · doi:10.1038/ncomms5628 · Cited by 76
Zinc-dependent Deacetylase (HDAC) Inhibitors with Different Zinc Binding Groups
Li, Y., Wang, F., Chen, X., Wang, J., Zhao, Y., Li, Y., & He, B. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190122144949 · Cited by 80
HDAC1/2/3 are major histone desuccinylases critical for promoter desuccinylation
Li, J., Lu, L., Liu, L., Ren, X., Chen, J., Yin, X., Xiao, Y., Li, J., Wei, G., Huang, H., et al. (2023) · Cell Discovery · doi:10.1038/s41421-023-00573-9 · Cited by 81
“…complexes are highly active for histone desuccinylation in vitro Previous elegant structural and functional studies demonstrated that a mammalian expressed minimal core complex consisting of HDAC3 and the deacetylase-activation domain from the SMRT corepressor is active in deacetylation 41 – 43 .”
BackgroundInnovative Strategies for Selective Inhibition of Histone Deacetylases
Maolanon, A. R., Madsen, A. S., & Olsen, C. A. (2016) · Cell Chemical Biology · doi:10.1016/j.chembiol.2016.06.011 · Cited by 72
Structural basis for the design and synthesis of selective HDAC inhibitors
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A specific mutation in TBL1XR1 causes Pierpont syndrome
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“Vucenik and Shamsuddin (2003) and Husna et al. (2010): IP 1 and IP 6; Bacic et al. (2010): IP 6; Watson et al. (2012) and Steger et al. (2003): IP4; Sheard et al. (2010) and Mosblech et al. (2011): IP5; Patergnani et al. (2011) and Somlyo and Somlyo (1994): IP3; Carey et al. (2004) and Abel et al.…”
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The Inositol Phosphate Signalling Network in Physiology and Disease
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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › 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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