Biological Roles of Corepressor Complexes 691
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Commentary 689 Biological roles and mechanistic actions of co- repressor complexes Kristen Jepsen1 and Michael G. Rosenfeld1,* 1Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 920393-0648, USA *Author for correspondence (e-mail: [email protected]) Journal of Cell Science 115, 689-698 (2002) © The Company of Biologists Ltd Summary Transcriptional repression, which plays a crucial role in allows DNA-binding proteins interacting with N-CoR or diverse biological processes, is mediated in part by non- SMRT to repress transcription of specific target genes. DNA-binding co-repressors. The closely related co- Both N-CoR and SMRT are important targets for cell repressor proteins N-CoR and SMRT, although originally signaling pathways, which influence their expression levels, identified on the basis of their ability to associate with and subcellular localization and association with other proteins. confer transcriptional repression through nuclear Recently, the biological importance of these proteins has receptors, have been shown to be recruited to many classes been revealed by studies of genetically engineered mice and of transcription factor and are in fact components of human diseases such as acute promyelocytic leukemia multiple protein complexes containing histone deacetylase (APL) and resistance to thyroid hormone (RTH). proteins. This association with histone deacetylase activity provides an important component of the mechanism that Key words: N-CoR, SMRT, Co-repressor, HDAC Introduction by unliganded nuclear receptors. The identification of a The regulation of gene expression by transcriptional control is 270 kDa protein associated with unliganded T3R-RXR required for many cellular events and for the proper heterodimers led to the cloning of N-CoR (Horlein et al., development of an organism. The essential nature of such 1995), and a similar approach identified a second, homologous control is highlighted by the large number of proteins devoted protein SMRT (Chen and Evans, 1995; Ordentlich et al., 1999; to regulation of transcription by RNA polymerase II. In Park et al., 1999). eukaryotes, these proteins number in the thousands and N-CoR and SMRT both contain a conserved bipartite include sequence-specific DNA-binding factors, the basal nuclear-receptor-interaction domain (NRID) (Li et al., 1997a; transcriptional machinary, chromatin-remodeling factors, Seol et al., 1996; Zamir et al., 1996) and three independent enzymes responsible for covalent modifications of histones and repressor domains that can actively repress a heterologous other proteins and cofactors that bridge DNA-binding factors DNA-binding domain (Chen and Evans, 1995; Horlein et al., and enzymes. Although activation of transcription has long 1995; Ordentlich et al., 1999; Park et al., 1999) (Fig. 1b). been recognized as an essential component of gene regulation, Further analysis of the NRIDs revealed that each contains a the realization that repression of transcription also plays a critical L-X-X-X-I-X-X-X-I/L motif, which includes the L/I- fundamental role has been appreciated only recently. X-X-I/V-I motif termed the CoRNR box (Hu and Lazar, 1999; Repressive factors use several distinct mechanisms, including Nagy et al., 1999; Perissi et al., 1999). This L-X-X-X-I-X-X- competition with activator proteins for DNA binding, X-I/L motif is similar to the L-X-X-L-L recognition motif sequestration of such activators, interaction with the core present in nuclear receptor coactivators (Heery et al., 1997; transcriptional machinery, DNA methylation and recruitment McInerney et al., 1998) but is predicted to form an extended of complexes that have histone deacetylase activity. Here we α-helix one helical turn longer than the coactivator motif. A focus on components of the co-repressor machinery that preference of RAR for SMRT and T3R for N-CoR (Cohen et depend, at least in part, on the actions of histone deacetylases, al., 2000) is due to specific sequences in the L-X-X-X-I-X-X- discussing primarily the nuclear receptor co-repressor (N-CoR) X-I/L motif (Hu et al., 2001) as well as to a T3R-specific and silencing mediator of retinoic and thyroid hormone interaction domain present in N-CoR but not SMRT (Cohen et receptors (SMRT) (Fig. 1a) (Chen and Evans, 1995; Horlein et al., 2001). al., 1995; Ordentlich et al., 1999; Park et al., 1999). Identification of histone deacetylase proteins Identification of nuclear receptor co-repressors Although co-repressor molecules contributing to the repression The knowledge that the thyroid hormone and retinoic acid of T3R and RAR had been identified, the mechanism by which receptors (T3R and RAR) actively repress transcription in the N-CoR and SMRT function remained elusive until several absence of their cognate ligands through transferable groups reported their association with mRpd3 and mSin3A repression domains (Baniahmad et al., 1992) led to the search and B, mammalian homologues of the yeast proteins for factors that might be required for effective gene repression Rpd3p/Histone Deacetylase 1 (msx mit1) and Sin3p (Heinzel 690 Journal of Cell Science 115 (4) A N-CoR SSMMRRTT TAFs IIA IIF IIJ TBP IIB TATA Pol II IIE Nuclear receptors IIH Histone and factor deacetylation B Repressor domains SANT domain HDAC3 HDAC4/5/7 HDAC3 N-CoR/SMRT RI A B RII RIII II I MyoD Bcl-6 Su(H)/RBP-J/ Nuclear Bcl-6 Transcription CBF1 receptors factor- AP-1, NFκB, SRF interaction domains Pit-1 Pit-1 Oct-1 Pit-1 PBX C Sin3a rpd3 p115 p60 p120 p65 RbAp48 p52 p37 p70 p29 N-CoR/SMRT N-CoR N-CoR N-CoR TBL1 p100 HDAC3 p110 p30 p250 p130 p53 p180 p46 BAF-155 HDAC2 SAP130 p53 Sin3a p48 p140 BAF-170 SAP30 p60 N-CoR SF3a120 N-CoR BAF-47 HDAC1 p35 p190 SRCAP p94 p63 KAP-1 p50 HDAC3 BRG-1 p50 p66 p220 p145 p64 p60 p40 p43 p96 p45 Biological roles of corepressor complexes 691 Fig. 1. (A) Transcriptional repression by nuclear receptors is identified by analysis of mutations that result in expression of regulated by recruitment of the co-repressors N-CoR and/or SMRT. regions of the yeast genome that are normally transcriptionally (B) The domains of N-CoR/SMRT. Repression domains (RI, RII, silenced (Nasmyth, 1982; Rine et al., 1979). Indeed, RIII) and SANT domains (A and B) are indicated, as are interaction Braunstein et al., prior to the identification of the class I domains for HDACs, nuclear receptors (I and II) and other and class II HDAC proteins, noted that overexpression of transcription factors. (C) N-CoR–SMRT compexes. Biochemical Sir2p in yeast cells produces histones that are under purification techniques have revealed several different complexes recruited by N-CoR and/or SMRT (Jones et al., 2001; Li et al., 2000; acetylated (Braunstein et al., 1993). This suggested, although Underhill et al., 2000; Wen et al., 2000; Guenther et al., 2000). in the absence of any biochemical evidence, that Sir2p has a role in histone deacetylation. Later studies identified nicotinamide adenine dinucleotide (NAD)-dependent ADP- et al., 1997; Nagy et al., 1997). Several years previously, the ribosyltransferase activity associated with the human Sir2p observations that acetylation of specific lysine residues in the homologue (Tsang and Escalante-Semerena, 1998), and N-termini of histones correlates with increased transcription extension of these studies revealed the surprising fact that Sir2p and that heterochromatic regions are generally hypoacetylated is in fact an NAD-dependent histone deacetylase (Imai et al., (Grunstein, 1990; Turner, 1993) had led to studies of the 2000; Landry et al., 2000; Smith et al., 2000). Interestingly, role of histone deactylase complex HDAC proteins in mammalian Sir2 can interact with and deacetylate the p53 transcriptional repression. Experiments in yeast identified two protein, reducing the transcriptional activity of p53 (Luo et al., HDAC complexes, HDA and HDB (Rundlett et al., 1996). 2001; Vaziri et al., 2001). The potential ability of this and other Further characterization of these complexes identified two classes of HDACs to deacetylate proteins other than histones closely related proteins, Hda1p and the previously cloned raises interesting possibilities for their ability to regulate gene transcriptional regulator, Rpd3p, (Vidal and Gaber, 1991), expression. respectively, as the proteins essential for histone deacetylase The precise roles of histone deacetylation in transcriptional activity (Rundlett et al., 1996). These proteins were the first repression are not fully understood. For instance, differential members of what are now known to be large families of histone display analysis of cells treated with the histone deacetylase deacetylases, which are classified on the basis of their inhibitor trichostatin A (TSA) revealed that the expression of homology to Rpd3p or Hda1p as class I or class II HDACs, just 2% of cellular genes (8 of 340 genes examined) changed, respectively (Gray and Ekstrom, 2001). despite an increase in core histone acetylation (Van Lint et al., Rpd3p is linked by epistasis to Sin3p (Rpd1) (Bowdish and 1996). Rpd3p-null strains in yeast have defects in both Mitchell, 1993; McKenzie et al., 1993; Vidal and Gaber, 1991), transcriptional repression and activation (Rundlett et al., 1996; which was initially identified in genetic screens for mutations Vidal et al., 1991) and in fact show increased repression at allowing expression of HO (homothallic gene) in the absence telomeric heterochromatin (Rundlett et al., 1996), revealing the of its activating protein,