title: A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation.
abstract: Nuclear receptor corepressors SMRT (silencing mediator of retinoid and thyroid receptors) and N-CoR (nuclear receptor corepressor) recruit histone deacetylase (HDAC) activity to targeted regions of chromatin. These corepressors contain a closely spaced pair of SANT motifs whose sequence and organization is highly conserved. The N-terminal SANT is a critical component of a deacetylase activation domain (DAD) that binds and activates HDAC3. Here, we show that the second SANT motif functions as part of a histone interaction domain (HID). The HID enhances repression by increasing the affinity of the DAD-HDAC3 enzyme for histone substrate. The two SANT motifs synergistically promote histone deacetylation and repression through unique functions. The HID contribution to repression is magnified by its ability to inhibit histone acetyltransferase enzyme activity. Remarkably, the SANT-containing HID preferentially binds to unacetylated histone tails. This implies that the SMRT HID participates in interpreting the histone code in a feed-forward mechanism that promotes and maintains histone deacetylation at genomic sites of SMRT recruitment.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6149, USA.
authors.forename: Jiujiu
authors.initials: J
authors.lastname: Yu
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishizuka
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Guenther
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000107:Acetylation; D020816:Amino Acid Motifs; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056985:Nuclear Receptor Co-Repressor 2; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D006657:Histones; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D012097:Repressor Proteins