title: A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness.
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 beta-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 TRbeta 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.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and Genetics, and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Guenther
authors.forename: W S
authors.initials: WS
authors.lastname: Lane
authors.forename: W
authors.initials: W
authors.lastname: Fischle
authors.forename: E
authors.initials: E
authors.lastname: Verdin
authors.forename: M A
authors.initials: MA
authors.lastname: Lazar
authors.forename: R
authors.initials: R
authors.lastname: Shiekhattar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D002846:Chromatography, Affinity; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005656:Fungal Proteins / Q000737:chemistry; D006367:HeLa Cells; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D056985:Nuclear Receptor Co-Repressor 2; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D015293:Transducin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D000099186:Histone Deacetylase 3
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D006655:Histone Deacetylases; D009687:Nuclear Proteins; D056985:Nuclear Receptor Co-Repressor 2; D010446:Peptide Fragments; D011994:Recombinant Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D015293:Transducin; D000099186:Histone Deacetylase 3; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; C119542:TBL1X protein, human; C066502:TUP1 protein, S cerevisiae; C485613:Tbl1x protein, mouse; C091023:gro protein, Drosophila