title: The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3.
abstract: Repression of gene transcription is linked to regulation of chromatin structure through deacetylation of core histone amino-terminal tails. This action is mediated by histone deacetylases (HDACs) that function within active multiprotein complexes directed to the promoters of repressed genes. In vivo, HDAC3 forms a stable complex with the SMRT corepressor. The SMRT-HDAC3 complex exhibits histone deacetylase activity, whereas recombinant HDAC3 is an inactive enzyme. Here we report that SMRT functions as an activating cofactor of HDAC3. In contrast, SMRT does not activate the class II HDAC4, with which it also interacts. Activation of HDAC3 is mediated by a deacetylase activating domain (DAD) that includes one of two SANT motifs present in SMRT. A cognate DAD is present in the related corepressor N-CoR, which can also activate HDAC3. Mutations in the DAD that abolish HDAC3 interaction also eliminate reconstitution of HDAC activity. Using purified components, the SMRT DAD is shown to be necessary and sufficient for activation of HDAC3. Moreover, the DAD is required both for HDAC3 to function enzymatically and for the major repression function of SMRT. Thus, SMRT and N-CoR do not serve merely as platforms for HDAC recruitment but function as an integral component of an active cellular HDAC3 enzyme.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, 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: O
authors.initials: O
authors.lastname: Barak
authors.forename: M A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics*; D008969:Molecular Sequence Data; D056985:Nuclear Receptor Co-Repressor 2; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D056985:Nuclear Receptor Co-Repressor 2; D012097:Repressor Proteins; D006655:Histone Deacetylases