A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness

Guenther, Matthew G.; Lane, William S.; Fischle, Wolfgang; Verdin, Eric; Lazar, Mitchell A.; Shiekhattar, Ramin

doi:10.1101/gad.14.9.1048

PreprintCited by 489Genomics and Chromatin DynamicsHistone Deacetylase Inhibitors ResearchEstrogen and related hormone effects

A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness

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Guenther, Matthew G., Lane, William S., Fischle, Wolfgang, Verdin, Eric, Lazar, Mitchell A., Shiekhattar, Ramin·2000·Genes & Development

DOI 10.1101/gad.14.9.1048PMC PMC316569

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Abstract

The corepressor SMRT mediates repression by thyroid hormone receptor (TR) as well as other nuclear hormone receptors and transcription factors. Here we report the isolation of a novel SMRT-containing complex from HeLa cells. This complex contains transducin β-like protein 1 (TBL1), whose gene is mutated in human sensorineural deafness. It also contains HDAC3, a histone deacetylase not previously thought to interact with SMRT. TBL1 displays structural and functional similarities to Tup1 and Groucho corepressors, sharing their ability to interact with histone H3. In vivo, TBL1 is bridged to HDAC3 through SMRT and can potentiate repression by TR. Intriguingly, loss-of-function TRβ mutations cause deafness in mice and humans. These results define a new TR corepressor complex with a physical link to histone structure and a potential biological link to deafness.

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HDAC3 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.”
From Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate (2012) · cites this paper as [24]
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)
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Authors: Guenther, M. G., Lane, W. S., Fischle, W., Verdin, E., Lazar, M. A., & Shiekhattar, R.
Affiliations: The Wistar Institute (US)
ORCID: Guenther, Matthew G.
Fischle, Wolfgang
Verdin, Eric
Lazar, Mitchell A.
Shiekhattar, Ramin
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2000-05-01
Volume: 14
Issue: 9
Pages: 1048-1057
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.14.9.1048
PMC: PMC316569
OpenAlex: W2172295707
Cited by: 489
References: 58
Citations by year: 2026: 3 · 2025: 8 · 2024: 14 · 2023: 10 · 2022: 11 · 2021: 6 · 2020: 16 · 2019: 15 · 2018: 11 · 2017: 12 · 2016: 22 · 2015: 13 · 2014: 16 · 2013: 14 · 2012: 16
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Max Planck Institute for Plasma Physics (submittedVersion)
Funders: V Foundation for Cancer Research
National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords: SMRT corepressor, HDAC3, TBL1, WD40 repeat proteins, thyroid hormone receptor, transcriptional repression, sensorineural hearing loss, histone deacetylase, histone H3, Tup1, nuclear receptors
MeSH terms: Histone Deacetylase 3, Amino Acid Sequence, Animals, Cell Line, Chromatography, Affinity, DNA-Binding Proteins, Fungal Proteins, Hearing Loss, Sensorineural, HeLa Cells, Histone Deacetylases, Humans, Molecular Sequence Data, Nuclear Proteins, Peptide Fragments, Recombinant Proteins, Repressor Proteins, Transfection, Transducin, Repetitive Sequences, Amino Acid, Saccharomyces cerevisiae Proteins, Mice, Basic Helix-Loop-Helix Proteins, Nuclear Receptor Co-Repressor 2

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A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness

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