Control of gene expression through regulation of the TATA-binding protein

Gene 255 (2000) 1–14 www.elsevier.com/locate/gene

Review

Control of gene expression through regulation of the TATA-binding protein B. Franklin Pugh * Center for Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 6802, USA Received 6 March 2000; received in revised form 9 June 2000; accepted 22 June 2000 Received by A.J. van Wijnen

Abstract The assembly of transcription complexes at eukaryotic promoters involves a number of distinct steps including chromatin remodeling, and recruitment of TATA-binding protein ( TBP)-containing complexes, the RNA polymerase II holoenzyme. Each of these stages is controlled by both positive and negative factors. In this review, mechanisms that regulate the interactions of TBP with promoter DNA are described. The first is autorepression, where TBP sequesters its DNA-binding surface through dimerization. Once TBP is bound to DNA, factors such as TAF 250 and Mot1 induce TBP to dissociate, while other factors such II as NC2 and the NOT complex convert the TBP/DNA complex into an inactive state. TFIIA antagonizes these TBP repressors but may be effective only in conjunction with the recruitment of the RNA polymerase II holoenzyme by promoter-bound activators. Taken together, the ability to induce a gene may depend minimally upon the ability to remodel chromatin as well as alleviate direct repression of TBP and other components of the general transcription machinery. The magnitude by which an activated gene is expressed, and thus repeatedly transcribed, might depend in part on competition between TBP inhibitors and the holoenzyme for access to the TBP/TATA complex. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Gene expression; General transcription factors; TATA-binding protein; TAFs; TBP; TFIID

1. Introduction The expression of a gene is dictated in part by the integration of cellular and environmental signals that control the activity of transcription regulatory proteins. How a gene responds to incoming signals will depend upon the physical state of the gene and the machinery that transcribes it. For purposes of discussion, the physical state of a gene can be put into one of three broad categories: repressed, basal, or induced. A repressed gene is essentially ‘off ’ and might be encased within chromatin such that the transcription machinery or any other factor cannot productively access the underlying promoter DNA. A basally expressed gene might reside within ‘open’ chromatin and thus be accessible to the transcription machinery. However, in the absence of a functional activator to recruit the transcription machinery, the gene Abbreviations: HAT, histone acetyl transferase; pol, RNA polymerase; TAF, TBP-associated factor; TBP, TATA binding protein. * Tel.: +1-814-863-8252. fax: +1-814-863-8595. E-mail address: [email protected] (B.F. Pugh)

is expressed at low levels. Induced genes are likely to reside in ‘open’ chromatin and be bound by transcriptional activators, which efficiently assemble the transcription machinery. Induced genes are typically expressed at high levels, although the level of induction will depend upon the behavior of transcriptional regulators present in the transcription complex. A typical eukaryotic promoter is composed of a myriad of binding sites for gene-specific regulatory proteins, as well as a core that is composed of a TATA box and/or an initiator element. The general transcription machinery assembles over the core promoter and initiates transcription at the initiator. The presence of the TATA-binding protein ( TBP) at the TATA box appears to be a pivotal intermediary step in transcriptional activation and deactivation. With the help of a functional promoter-bound transcriptional activator, TBP is recruited to the TATA box, along with a number of other regulatory proteins (Fig. 1). This activator/TBP complex subsequently or simultaneously recruits the RNA polymerase (pol ) II holoenzyme, allowing it to

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B.F. Pugh / Gene 255 (2000) 1–14

Fig. 1. Simplified diagram of two of the major steps in transcription complex assembly. Activators bound to their cognate sites on promoter DNA recruit TFIIA (A) and the TBP/TAF complex TFIID to the core promoter. This complex then enables the pol II holoenzyme to bind. Alternative II non-TAF assembly pathways may also exist. II

effectively compete out the binding of TBP inhibitors. Once the activating signal is removed, rendering the activator non-functional, TBP inhibitors may be at a competitive advantage over the pol II holoenzyme. It is this positive and negative regulation of TBP/TATA interactions that is the subject of this review. Unfortunately, space limitations preclude detailed coverage of this intensively studied topic. Additional coverage can be found in a number of outstanding reviews (Hernandez, 1993; Burley and Roeder, 1996; Orphanides et al., 1996; Hampsey, 1998; Lee and Young, 1998). 2. Recruitment of the transcription machinery can be rate-limiting in gene expression Despite the ability of the general transcription machinery to recognize the core promoter in vitro, in

general, the preinitiation complex is not assembled in the cell unless facilitated by transcriptional activators ( Fig. 1). This notion has been confirmed through in-vivo footprinting and formaldehyde cross-linking experiments with yeast, in which TBP was found to be crosslinked with promoter DNA only in the presence of an activator (Selleck and Majors, 1987; Kuras and Struhl, 1999; Li et al., 1999). Inactivity of the core promoter may be caused in part by it being encased within nucleosomes, possibly rendering it inaccessible to the transcription machinery. Activators may facilitate chromatin accessibility by recruiting one or more of a variety of chromatin remodeling factors ( Utley et al., 1998). However, the general transcription machinery may be endowed with chromatin modifying and remodeling activity (Mizzen et al., 1996; Wilson et al., 1996), and so the chromatin structure may not be entirely responsi-

B.F. Pugh / Gene 255 (2000) 1–14

ble for preventing access of the general transcription machinery to the core promoter. Several lines of evidence suggest that even if promoter DNA is accessible to the general transcription machinery, the transcription complex assembles inefficiently in the absence of activators. Fusion of TFIID subunits, or pol II holoenzyme components to a sequence-specific DNA-binding domain, generates high levels of activator-independent gene expression, whereas their fusion to an activation domain does not (Barberis et al., 1995; Chatterjee and Struhl, 1995; Klages and Strubin, 1995; Xiao et al., 1995; Farrell et al., 1996; Gaudreau et al., 1997; Keaveney and Struhl, 1998). These fusion experiments demonstrate that high levels of transcription can be obtained in the absence of a promoter-bound activator, as long as one component of the transcription machinery has a sequence-specific DNA-binding capability beyond core promoter recognition. Such by-pass experiments demonstrate that recruit-

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ment of the general transcription machinery is an important step in the activation process. A commonly held view is that TBP is one of the first general transcription factors to be recruited to a promoter.

3. Assembly of the TATA-binding protein and associated factors 3.1. TBP family Of the multitude of proteins that constitute a transcription complex, TBP stands out as one of the few that are highly conserved amongst all eukaryotes and archaea; it is not found in eubacteria. The 180 carboxylterminal amino acids of TBP form a molecular saddle that straddles the minor groove of the TATA box (Burley and Roeder, 1996) ( Fig. 2). This domain also binds activators, TBP-associated factors ( TAFs), repres-

Fig. 2. Space-filling model of the core 180 carboxyl-terminal amino acids of TBP (red ) bound to a TATA DNA (black and yellow). The yeast TBP structure is shown, although its structure is highly conserved from archaea to humans.

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sors, and general transcription factors. TBP or its homologs are required for the expression of possibly all genes, including those transcribed by pol I and III. However, two in-vitro systems directed by either the sequencespecific activator YY1 or the TAF-containing TFTC complex support pol II transcription in the absence of TBP, which opens up the intriguing possibility that some genes might not require TBP (or TBP-like factors) ( Usheva and Shenk, 1994; Wieczorek et al., 1998). In addition to TBP, multi-cellular eukaryotes contain at least one TBP-related factor. The first of these to be discovered was TRF1, which displays a neuronal and testis-restricted expression pattern in Drosophila and targets pol II and III genes (Hansen et al., 1997; Holmes and Tjian, 2000; Takada et al., 2000). Originally shown to bind to a TATA element (Crowley et al., 1993), more recent evidence suggests that TRF1 preferentially binds to, and directs transcription from, a TC-rich promoter element. The ability of TBP and TRF1 to bind differentially to distinct DNA elements is surprising given the strong conservation of their DNA-binding surfaces. TRF1 orthologs are not apparent in the sequenced genomes of yeast or worms and thus might be specific to metazoans or possibly just insects since additional metazoan orthologs have not been identified. Interestingly, in Drosophila, only TRF1 reconstitutes pol III transcription of tRNA and U6 snRNA genes ( Takada et al., 2000), whereas in yeast and humans, TBP serves this role ( Kassavetis et al., 1992; Wang and Roeder, 1995). Both TBP and TRF1 nevertheless utilize the pol III-specific TAF, BRF. At pol II promoters, TRF1 is associated with a largely uncharacterized set of factors termed neuronal TAFs (nTAFs) (Hansen et al., 1997). TRF2 (also known as TRP, TLP, and TLF ) is more distantly related to TBP and TRF1, and has been identified in worms, flies, and a variety of vertebrate tissues ( Wieczorek et al., 1998; Maldonado, 1999; Moore et al., 1999; Ohbayashi et al., 1999; Rabenstein et al., 1999; Teichmann et al., 1999). Unlike TRF1, the predicted DNA-binding surface of TRF2 shows little conservation with TBP, suggesting that it may utilize promoter elements distinct from TATA, if it binds DNA at all. In-vitro experiments suggest that TRF2 might function as a transcriptional repressor, possibly by competing with TBP or TFIID for binding TFIIA (Moore et al., 1999; Teichmann et al., 1999). Exactly what role these TBP related factors play in multi-cellular organisms is unclear, although they might endow the transcription machinery with additional flexibility for genespecific control during development and differentiation.

yet unlike nearly all sequence-specific transcription factors, it binds the DNA’s minor groove instead of the major groove ( Kim et al., 1993a,b). If high-specificity DNA recognition were the sole function of TBP, it picked the wrong side of the DNA to interact with. Unlike the major groove, specificity determinants are minimal in the minor groove. Second, TBP is required at promoters that lack a TATA box (Pugh and Tjian, 1991), which stands in contrast to sequence-specific activators that are often not required at promoters lacking their recognition sites. None the less, TBP appears to be bound to the DNA in the −30 region, regardless of the underlying sequence ( Zenzie-Gregory et al., 1993). Apparently, TATA-less promoters have evolved mechanisms by which promoter specificity of TBP is achieved through direct and indirect interactions with sequence-specific factors such as TAF s and activators. However, promoters that utilize II a TATA box can be very sensitive to mutations in it, which indicates that TBP/TATA interactions are important. Perhaps at these TATA-dependent promoters, TBP does not fully utilize the same protein–protein interaction specificity determinants found at TATA-less promoters. Third, mutations in the DNA-binding surface of TBP weaken DNA binding in vitro and activated transcription in vivo, but stimulate activator-independent transcription in vivo (Arndt et al., 1995; Jackson-Fisher et al., 1999; Geisberg and Struhl, 2000). The latter effect may be due to the inability of TBP to autorepress itself through dimerization of its DNA-binding surface (Jackson-Fisher et al., 1999). Mutations in this region might destabilize dimers to a greater extent than DNA binding, resulting in a net increase in activator-independent promoter binding. Thus, TBP appears to function both positively and negatively in transcription. What essential activity does the TBP family provide that no other protein can replace? Once TBP is bound to DNA, it is thought to nucleate the assembly of the remainder of the general transcription machinery. If this is its sole function, what advantage does minor groove binding provide that the major groove cannot? Most proteins that selectively bind to the minor groove appear to function primarily to bend DNA. TBP is no different; DNA entering and exiting TBP are nearly at right angles to each other ( Kim et al., 1993a,b) (Fig. 2). DNA bending may be important in bringing factors bound upstream of TBP in contact with protein bound downstream. 3.3. TBP exists in a variety of functionally distinct complexes

3.2. Contradictions of TBP TBP is full of apparent contradictions. First, it binds the TATA box with a fairly high affinity (K ~1 nM ), D

TBP is associated with a variety of complexes ( Fig. 3), some of which function with specific RNA polymerases (Goodrich and Tjian, 1994). The four-

B.F. Pugh / Gene 255 (2000) 1–14

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Fig. 3. TBP and TAFs reside within a variety of complexes. TFIID, SAGA/PCAF and TFTC are similar in composition, and function at pol-II transcribed promoters. SL1 (human TAF nomenclature) and TFIIIB (yeast nomenclature) are specific for pol I and III, respectively. SNAP I c (human SNAP nomenclature) targets snRNA promoters. Mot1 and NC2 represent repressed TBP. SNAP , NC2, and Mot1 may interact with c TBP primarily on DNA (indicated by a line). Where homologous subunits have been identified in multiple organisms but have distinct names, their names are preceded by either h, d, or y for humans, Drosophila, and yeast, respectively. Numbered subunits in TFIID, SAGA/PCAF, and TFTC refer to TAF s. Names in parentheses reflect alternative names. Subunits that are shared among distinct complexes are colored similarly. II

subunit SL1 TBP/TAF complex functions exclusively I at pol I-transcribed promoters. TFIID is a TBP/TAF II complex specific for promoters of mRNA genes. The TFIIIB TBP/TAF complex contains three subunits III and targets pol III-transcribed promoters. Subsets of pol II and III-transcribed genes appear to be regulated by alternative TBP-containing complexes, some of which may be less stably assembled than TFIID. For example, SNAP is a multisubunit complex that c activates human snRNA promoters through interactions with TBP (Henry et al., 1995). While SNAP has not c been characterized in other organisms, the presence of its DNA-binding site in Drosophila but not yeast snRNA genes, indicates that it may be restricted to metazoans. Examples of TBP complexes that negatively regulate

transcription include Mot1, NC2, and the TFIID-like chromatin remodeling complexes SAGA (Inostroza et al., 1992; Auble et al., 1994; Goppelt et al., 1996; Chicca et al., 1998; Sterner et al., 1999; Belotserkovskaya et al., 2000). Their regulation of TBP is discussed further below. Whether TBP ever functions in the absence of TAF s is of considerable interest. In yeast, TBP can be II readily isolated free of TAF s. Many of the TAF s, II II while essential for cell viability, are not strictly required for activated transcription of all genes (Moqtaderi et al., 1996a; Apone et al., 1998). TBP (but not TAF s) is II nevertheless recruited to these TAF-independent promoters as measured by in-vivo formaldehyde crosslinking assays, whereas both are recruited to

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TAF -dependent promoters ( Kuras et al., 2000; Li et al., II 2000). Interestingly, TAF s are recruited to TAF-depenII dent promoters even in the absence of a functional TBP, which implies that TAF s recruit TBP and not vice II versa (Li et al., 2000). Under stress conditions, such as heat shock, TAF-independent promoters show increased occupancy by TAF s ( Kuras et al., 2000). This suggests II that TAF dependency of a promoter may be a function of the physiological state of the cell as well as its underlying DNA sequences. The apparent dispensability of some TAF s might reflect the presence of other II factors that are functionally redundant to the TAF s. II For example, activators might interact with components of the pol II holoenzyme, which in turn recruit TBP. It is not known why TBP exists in a variety of complexes, although in general, many of the positively acting factors associated with TBP are likely to direct TBP to the appropriate promoter, while many of the negatively acting factors might remove TBP from DNA. In archaea, TAF homologs have not been identified II from any of the sequenced genomes. It will be interesting to determine how archaea function with a minimal transcription machinery. 3.4. Properties of TFIID TFIID is composed of TBP and approximately 14 distinct TAF subunits, which have been largely characII terized in yeast (y), Drosophila (d ), and humans (h) ( Table 1), and are turning out to have a variety of informative structures and activities. High-resolution structures of the TFIID complex and its regulators have yet to be determined. However, a number of highresolution structures of subunit domains, including TBP, dTAF 62/dTAF 42, hTAF 28/hTAF 18, II II II II dTAF 250, yTFIIA, and hTFIIB, have provided an II enormous insight into the function of these proteins (Nikolov and Burley, 1994a,b; Nikolov et al., 1995; Geiger et al., 1996; Tan et al., 1996; Xie et al., 1996; Birck et al., 1998; Liu et al., 1998a; Jacobson et al., 2000). Cryo-electron microscopy has provided a low ˚ resolution image of TFIID, revealing a tri-lobed 35 A structure with TBP in the center (Andel et al., 1999; Brand et al., 1999a). The use of subunit-specific antibodies should soon allow for the arrangement of TAF s II within TFIID to be determined. 3.4.1. TAF coactivators II A number of TAF s have been identified as direct II transcriptional targets of activators in vitro. A variety of activators in the ‘acidic’ class, including p53 and VP16, interact with dTAF 40 (Goodrich et al., 1993; II Farmer et al., 1996). The broadly expressed Sp1 activator interacts with dTAF 110 (Hoey et al., 1993), the II neurologic transcriptional activator NTF1 activates through dTAF 150 (Chen et al., 1994), hormone recepII

tors function through a number of TAF s including II hTAF 28, hTAF 30, and hTAF 135 (Jacq et al., 1994; II II II May et al., 1996; Mengus et al., 1997), and a variety of activators target hTAF 55 (Chiang and Roeder, 1995). II 3.4.2. TFIID–promoter interactions TFIID occupies 70–80 bp of DNA surrounding the transcriptional start site. In addition to TBP/TATA contacts, a number of TAF s bind DNA to help position II TFIID. These include dTAF 150, which binds to the II initiator element surrounding to the transcriptional start site ( Verrijzer et al., 1994), and dTAF 60/ dTAF 40, II II which contacts a DPE element located downstream of the transcriptional start site (Burke and Kadonaga, 1997). TAF /promoter contacts might direct TFIID II preferentially to certain promoters. 3.4.3. Histone-like TAF s II At least six different TAF s and a number of other II TBP-interacting proteins possess histone-like folds. The first to be identified were dTAF 42 and dTAF 62, which II II form a heterotetramer that is structurally equivalent to the histone H3/H4 tetramer ( Xie et al., 1996). hTAF 135 and hTAF 20 heterodimerize and are strucII II turally related to histones H2A and H2B, respectively (Gangloff et al., 2000). hTAF 28 and hTAF 18 form a II II histone-like heterodimer, which together might structurally resemble the histone-fold motifs of Spt3 (Birck et al., 1998). While many of these histone-like pairs also interact with each other, it is not clear whether higherorder histone octamer-like structures form, and if so, in what arrangement or stoichiometry they assemble. Interestingly, these histone-like TAF s or their homologs II (i.e. Ada1 and Spt3) and yTAF 90 appear to be integral II components of the yeast SAGA (PCAF and TFTC in humans) chromatin remodeling complex (Imhof et al., 1997; Grant et al., 1998; Martinez et al., 1998b). Whether Spt3 can functionally replace hTAF 28/ II hTAF 18 is unknown, although both bind to TBP II ( Eisenmann et al., 1992; Mengus et al., 1995). 3.4.4. TAF 250 II The hTAF 250 subunit of TFIID (yTAF 145 or 130 II II in yeast) possesses histone acetyltransferase (HAT ) activity (Mizzen et al., 1996). The functionally equivalent factor in SAGA and TFTC is Gcn5 (PCAF in the PCAF complex). An intriguing possibility is that TFIID and SAGA/PCAF/TFTC represent functionally similar complexes (Fig. 3). Each might possess distinct and possibly overlapping roles in gene control. TFIID- or SAGA/PCAF/TFTC-specific subunits might direct each to different sets of promoters, whereas interactions with common subunits might lead to recruitment of either complex. HATs have the capacity to acetylate and thus neutralize the positively charged lysine residues in the amino

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B.F. Pugh / Gene 255 (2000) 1–14 Table 1 TAF subunits of TFIIDa II Yeast yTAF

Drosophila dTAF II

Human hTAF II

Other TAF complexes II

Interactions

1501 TSM12

1503

1504 CIF1505

hTFTC6

DNA (Inr)3 Activatorsc7

1458 1301 plus Bdf1/29

25010 23011

25012,13 CCG114

901,8

8520 8021

10022-24

6828 6129

30a30 28.2231

6729

II

Other properties

TBP TAF7 s TFIIF15Histone Cyclin D116

Destabilizes TBP/TATA Protein kinase17 acetyltransferase18 Double bromodomain binds acetylated H4 tails19 BDF1 and BDF2 are distinct genes9

hTFTC25 ySAGA26

dTAF 11020 II TFIIF23

Related protein in PCAF is PAF65b6,27 Contains WD-40 repeats

20/1532,33

hTFTC25 ySAGA26 hPCAF27

Histone H2B-like36 Histone fold partner is hTAF 13535 II hTAF 15 is derivative of hTAF 2032 II II

?

5537,38

hTFTC25

TBP32,34 hTAFC 13535 II hTAF 3032,33 II hTAF 2832,33 II hTAF 8032 II Activators37,39 TAFs37,39

6540

?

?

601

6231 6041

8042 7041

hTFTC25 ySAGA26 hPCAF27

TAF 4243 II hTAF 2032 II TAF 25041 II TFIIE/F42 DNA (DPE)44

Histone H4-like Histone fold partner is dTAF 4243 II Related protein in PCAF is PAF65a27

4840 Tsg234

11045

13546 13022 10547

hTFTC25

hTAF 2035 II TFIIA48 TAF 2507 II Spl22,45

Histone H2A-like Histone fold partner is hTAF 3035 II Coactivator of Q-rich activators22,45,49 Coactivator for viral activators50 Coactivator for hormone receptors46 hTAF 105 is tissue-specific47 II Related protein in SAGA is ADA135

4740

?

?

4051

30b30

2833

Vitamin D receptor52 Retinoid receptor53

Histone-like54 Histone fold partner is hTAF 1854 II Related protein in SAGA/PCAF/TFTC is Spt354

3055,56

?

AF-9 ENL

yTFIIF55,56 ySWI/SNF55,56 yNuA357

Coactivator for hormone receptors52,53

2551 2329

1658 2458

3059

hTFTC25 ySAGA26 hPCAF27

Coactivator for estrogen receptors59 dTAF 16 and dTAF 24 have distinct genes58 II II

1929 Fun81

?

1833

1729

4231 4060

3261 3162

Histone H4-like54 Histone fold partner is hTAF 2854 II Related protein in SAGA/PCAF/TFTC is Spt354 hTFTC25 ySAGA26 hPCAF27 hSTAGA63

TFIIV60 Activators60–62,64 DNA(DPE )44 Spt63

Histone H3-like43 Coactivator for ‘acidic’ activators60–62,64

a Reference citations are denoted by the following superscript numbers: 1Poon et al., 1995; 2Ray et al., 1991; 3Verrijzer et al., 1994; 4Martinez et al., 1998a; 5Kaufmann et al., 1998; 6Brand et al., 1999b; 7Chen et al., 1994; 8Reese et al., 1994; 9Matangkasombut et al., 2000; 10Weinzierl et al., 1993a; 11Kokubo et al., 1993a; 12Ruppert et al., 1993; 13Hisatake et al., 1993; 14Sekiguchi et al., 1988; 15Ruppert and Tjian, 1995; 16Adnane et al., 1999; 17Dikstein et al., 1996a; 18Mizzen et al., 1996; 19Jacobson et al., 2000; 20Kokubo et al., 1993b; 21Dynlacht et al., 1993; 22Tanese et al., 1996; 23Dubrovskaya et al., 1996; 24Tao et al., 1997; 25Wieczorek et al., 1998; 26Grant et al., 1998; 27Ogryzko et al., 1998; 28Walker et al., 1996; 29Moqtaderi et al., 1996b; 30Yokomori et al., 1993a; 31Kokubo et al., 1994; 32Hoffmann and Roeder, 1996; 33Mengus et al., 1995; 34Reese et al., 2000; 35Gangloff et al., 2000; 36Hoffmann et al., 1996; 37Chiang and Roeder, 1995; 38Lavigne et al., 1996; 39Lavigne et al., 1999; 40Sanders and Weil, 2000; 41 Weinzierl et al., 1993b; 42Hisatake et al., 1995; 43Xie et al., 1996; 44Burke and Kadonaga, 1997; 45Hoey et al., 1993; 46Mengus et al., 1997; 47 Dikstein et al., 1996b; 48Yokomori et al., 1993b; 49Felinski and Quinn, 1999; 50Mazzarelli et al., 1995; 51Klebanow et al., 1996; 52Mengus et al., 2000; 53May et al., 1996; 54Birck et al., 1998; 55Cairns et al., 1996; 56Henry et al., 1994; 57John et al., 2000; 58Georgieva et al., 2000; 59Jacq et al., 1994; 60Goodrich et al., 1993; 61Klemm et al., 1995; 62Lu and Levine, 1995; 63Martinez et al., 1998b; 64Thut et al., 1995.

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terminal ‘tails’ of histones. A possible consequence of charge neutralization is the decondensation and increased accessibility of the resident chromatin. Particular histone acetylation patterns are also recognized by bromodomain-containing proteins such as TAF 250 (Jacobson et al., 2000). This promoter proxiII mal histone acetylation might help direct TAF 250 to II load TBP at the promoter. In addition to HAT activity, hTAF 250 possesses II two kinase domains which phosphorylate itself and the general transcription factor TFIIF (Dikstein et al., 1996a). In yeast, the second kinase domain is coded by either of two genes, BDF1 and BDF2 (Matangkasombut et al., 2000). Some promoters are highly dependent upon yTAF 145, and this dependence is conferred through a II yTAF 145-responsive region of the promoter (Shen and II Green, 1997). There is no evidence, however, that yTAF 145 binds to this region to activate transcription. II Instead it appears that this region confers a repressive state upon the promoter, which is relieved by yTAF 145. The presence of HAT activity in at least II TAF 250 is consistent with a potential anti-repressor II function, and mutations in the HAT domain compromise the expression of specific genes in vivo (Dunphy et al., 2000). However, despite the guilt by association, it still remains to be determined whether TAF 250 II (yTAF 145) activates transcription by remodeling II chromatin. Like TBP, TAF 250 has its own apparent contradicII tions. hTAF 250 is a central scaffold upon which II TAF s assemble (Chen et al., 1994); yet, in yeast, II yTAF 145 is required for transcription of only 17–27% II of the genome (Holstege et al., 1998; Lee et al., 2000). The apparent limited requirement of yTAF 145 may II indicate that most genes do not require a yTAF 145 II function. Alternatively, many genes might function in the context of any one of a number of alternative TAF complexes, such as TFIID and SAGA. If so, then II only in the absence of these alternative TAF complexes II

will the full involvement of a particular TAF be revealed II (Lee et al., 2000) . While yTAF 145 is required for transcriptional actiII vation of at least some genes, in apparent contradiction, its amino-terminal domain functions to dissociate TBP from DNA (Bai et al., 1997; Kokubo et al., 1998) and thus might also function as a TBP repressor. It has not yet been established whether this inhibitory activity functions in vivo. Interestingly, the amino-terminal domain of dTAF 250 binds to the concave DNAII binding surface of TBP, forming a structure that apparently mimics DNA, and thus competing with DNA for binding TBP (Liu et al., 1998a).

4. Regulation of TBP/TATA complexes Once bound to DNA, TBP has the capacity to nucleate transcription complex assembly, even on TATA-less DNA. This may not occur in vivo to any significant extent unless directed to do so by sequencespecific activators. How, then, is TBP prevented from using its high-affinity DNA-binding surface to promiscuously bind DNA? One possibility is that chromosomal DNA is made inaccessible by histones (Fig. 4). However, chromatin remodeling complexes abound within the cell, and some are tethered to TBP. Moreover, sequence-specific activators must have unfettered access to DNA if they are to target specific genes. Therefore, except in cases of gene-specific repression, chromatin in general might be fairly accessible to transcription factors including TBP. If so, TBP would require further regulation. Unregulated binding of TBP to DNA may be minimized by repressors that bind TBP and block its association with DNA and/or repressors that bind TBP/DNA complexes and either induce TBP dissociation or prevent TBP from progressing on to form productive transcription complexes. Most TBP repressors identified thus far appear to act upon pre-formed TBP/DNA complexes. One mechanism that might pre-

Fig. 4. Possible mechanisms by which TBP/DNA interactions may be repressed.

B.F. Pugh / Gene 255 (2000) 1–14

vent TBP from accessing DNA in vitro and in vivo is dimerization. 4.1. TBP dimerization One of the first structural glimpses of the general transcription machinery was that of TBP dimers. In the absence of DNA, the saddle-shaped TBP core crystallized into a dimer, resulting in a ‘handshake’ of the carboxyl-terminal stirrups and a steric occlusion of the DNA-binding surface (Nikolov et al., 1992). Subsequent biochemical studies demonstrated that TBP dimers exist when not bound to DNA and generate a kinetic block to DNA binding (Coleman et al., 1995; Coleman and Pugh, 1997). Mutations in the dimer interface that decrease the stability of dimers in vitro generate increased levels of activator-independent gene expression in vivo (Jackson-Fisher et al., 1999). In addition, there is a strong correlation between TBP dimer stability and protection of TBP from degradation in vivo. Apparently, TBP dimerization prevents both unregulated access of TBP to DNA and its own degradation. The latter is a typical physiological response, where incompletely assembled complexes are rapidly recycled in vivo. Some evidence suggests that TFIID dimerizes via a TBP interface ( Taggart and Pugh, 1996), although cryoelectron microscopy studies indicate a monomer when in a highly purified state (Brand et al., 1999a). If TBP dimerization helps prevent the expression of some uninduced genes, it follows that transcriptional activators will directly or indirectly target TBP for dimer disruption. Consistent with this notion, TBP and TFIID dimers are specifically disrupted by TFIIA (Coleman et al., 1999), a general transcription co-activator that is well known to assist in the loading of TBP on to DNA. 4.2. Mot1 While dimerization provides one mechanism to prevent unregulated access of TBP to DNA, other mechanisms operate on TBP/DNA complexes. Mot1, a member of the SNF2 family of DNA-dependent ATPases, readily associates with TBP/TATA complexes (Auble and Hahn, 1993; Chicca et al., 1998). Mot1 uses the energy of ATP hydrolysis to dissociate TBP from DNA and itself from TBP, thereby freeing up TBP to be re-engaged. Mot1 appears to be more prolific at weaker TATA and non-TATA sequences. Under in-vitro conditions, where non-specific DNA binding by TBP is made to compete with productive promoter-specific binding, Mot1 stimulates transcription at that promoter, possibly by freeing up TBP that is sequestered on the non-specific DNA (Muldrow et al., 1999). Genetic studies also suggest a role for Mot1 in redistributing TBP between weak and strong TATA boxes (Collart, 1996).

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Temperature-sensitive Mot1 mutations at the restrictive temperature cause an increased occupancy of TBP at promoter sites in vivo, which further implicates Mot1 in removal of TBP from promoter DNA (Li et al., 1999). Interestingly, Mot1 appears to act on TBP lacking TAFs in both the pol II and III in-vitro transcription systems, but not on TFIID (Chicca et al., 1998). It is possible, that Mot1 primarily targets TBP/TATA complexes that lack TAFs, and other mechanisms, such as the amino-terminal domain of TAF 250, are employed II to target TBP within TFIID. In addition to TAFs, TFIIA also counteracts Mot1 repression. Once TBP has loaded on to DNA as directed by an activator, the activator/TBP complex recruits the pol II holoenzyme. The activator/TBP complex may serve as a reusable launching pad through multiple rounds of transcription. At some point, when the gene-inducing signal is removed, the gene must be shut down. The activator might disengage from the promoter or in some way be rendered incompetent to efficiently recruit the pol II holoenzyme. TFIIA might be unable to efficiently ward off Mot1, leaving TBP susceptible to attack by Mot1 and other repressors. Consistent with this possibility, TBP mutations that impair holoenzyme recruitment (via TFIIB) are unable to stably load on to promoters, even in the presence of activators (Li et al., 1999). 4.3. NC2 NC2 is composed of two subunits each of Dr1 and Drap1, that interact via histone fold-like motifs ( Inostroza et al., 1992; Goppelt et al., 1996; Yeung et al., 1997). The Drap1 gene was genetically identified in yeast as BUR6, in which certain mutations cause elevated levels of basal (activator-independent) transcription of the SUC2 gene (Prelich, 1997). NC2 binds TBP/TATA complexes in vitro, and genetic interactions with TBP have been defined in vivo (Cang et al., 1999). NC2 does not appear to dissociate TBP/TATA complexes, but instead inhibits the incorporation of TFIIA and/or TFIIB into the assembling transcription complex. A single point mutation in TFIIA, which destabilizes its interactions with the TBP/TATA complex, suppresses the NC2 requirement for cell viability in yeast ( Xie et al., 2000). This is consistent with a physiological role for competitive interactions between TFIIA and NC2 for TBP binding. NC2 may prevent the loading of the pol II holoenzyme and thus preinitiation complex assembly. At some promoters, sequence-specific repressors might direct NC2 to repress TBP (Ikeda et al., 1998). 4.4. NOT complex The NOT complex is composed of Not1, Not2, Not3, Not4, Not5, Caf1 and Ccr4 (Collart and Struhl, 1994;

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Liu et al., 1998b; Bai et al., 1999). Like NC2, the NOT complex does not dissociate TBP from DNA but appears to prevent it from recruiting the pol II holoenzyme, possibly by preventing productive interactions of Spt3 with the TBP/DNA complex (Hampsey, 1998; Lee et al., 1998). Mutations in the NOT genes lead to elevated levels of basal transcription and thus implicate the NOT complex in establishing, in part, the low level of basal transcription observed in the absence of activators. In yeast, the NOT complex appears to preferentially repress TATA-less promoters (Oberholzer and Collart, 1999). 4.5. TFIIA Our understanding of TFIIA’s role in transcription regulation has now matured. Earlier in-vitro studies indicated that TFIIA was largely dispensable for activator-independent transcription in vitro (Cortes et al., 1992; Sayre et al., 1992; Ozer et al., 1994; Sun et al., 1994; DeJong et al., 1995; Hansen and Tjian, 1995). We now know that TFIIA plays many roles in transcription. In particular, TFIIA is essential for transcriptional activation and anti-repression of many genes. In-vitro transcription reactions, by their very nature, were optimized to produce maximum (and often activator-independent) transcription. By removing a slate of TBP inhibitors through biochemical fractionation, TFIIA itself became superfluous. TFIIA is a three-subunit complex (two in yeast) that is coded for by two genes. Like TBP, there is a family of TFIIA genes, one of which is predominantly expressed in the testis ( Upadhyaya et al., 1999; Ozer et al., 2000). TFIIA binds TBP opposite the side where TBP dimerizes and interacts with TFIIB. Binding of TFIIA to autorepressed TBP dimers induces dimer dissociation and accelerates the kinetics of DNA binding (Coleman et al., 1999). The association of TFIIA with TBP/TFIID is inefficient, and may be enhanced by transcriptional activators. If transcriptional activators function, in part, to coalesce TFIIA and TFIID, it becomes clear that TFIIA plays a critical role in transcriptional activation. In fact, TFIIA binds to acidic viral activators such as Zta and VP16 (Ozer et al., 1994; Kobayashi et al., 1995). Once TBP/TFIID is bound at the promoter, TFIIA helps prevent inhibitors from dissociating TBP (e.g. Mot1 and TAF 250) or inactivating TBP (e.g. II NC2) (Inostroza et al., 1992; Kokubo et al., 1998; Ozer et al., 1998). In addition, TFIIA directly stabilizes the interactions between TBP and TATA, and induces conformational changes in the TFIID complex that may make it competent to receive the pol II holoenzyme (Chi and Carey, 1996).

5. Conclusions The importance of TBP/promoter interactions is reflected in the many different proteins that directly

regulate TBP. Promoter association might be negatively autoregulated through dimerization, which is reversed by TFIIA. Once bound to DNA, other negative factors such as NC2 and the NOT complex might antagonize transcription complex assembly, thereby allowing additional negative factors like Mot1 and TAF 250 to induce II TBP to dissociate. However, the coordinate action of sequence-specific transcriptional activators, TFIIA, and the pol II holoenzyme might outcompete these negative factors, thereby leading to productive transcription complex assembly. Genetic and biochemical studies indicate that there is extensive interplay among the positive and negative TBP regulatory factors. Yet, little is known about which players regulate TBP’s interaction at a particular promoter and the order of events. Many questions remain. For example, is Mot1 recruited to certain promoters only, or can Mot1 target TBP at any promoter that is not blocked by the presence of positive factors like TFIIA? Does the amino-terminal domain of TAF 250 II function to remove TBP from DNA in vivo when TFIIA is no longer associated? Is the TAF 250 amino-terminal II domain redundant in any way with Mot1? Does NC2 and Mot1 act in concert or independently to remove TBP? Is SAGA and the TAF complex functionally II redundant at some promoters but not at others? Is promoter occupancy of SAGA and the TAF complex II mutually exclusive? What replaces TAF s at TAF-indeII pendent promoters? The assembly and disassembly of TBP at a promoter is but one of a number of important regulatory points in gene expression. While positive and negative factor interplay may impinge upon TBP at every promoter, the extent to which these interactions limit the expression of any gene will likely vary from gene to gene, and from one physiological state of the cell to another. The expression level of any one gene under any particular physiological state may be rate-limited by subcellular translocation of transcription factors, post-translational modifications, chromatin remodeling, TBP loading, and/or recruitment of the pol II holoenzyme.

References Adnane, J., Shao, Z., Robbins, P.D., 1999. Cyclin D1 associates with the TBP-associated factor TAF(II )250 to regulate Sp1-mediated transcription. Oncogene 18, 239–247. Andel 3rd, F., Ladurner, A.G., Inouye, C., Tjian, R., Nogales, E., 1999. Three-dimensional structure of the human TFIID–IIA–IIB complex. Science 286, 2153–2156. Apone, L.M., Virbasius, C.A., Holstege, F.C., Wang, J., Young, R.A., Green, M.R., 1998. Broad, but not universal, transcriptional requirement for yTAFII17, a histone H3-like TAFII present in TFIID and SAGA. Mol. Cell 2, 653–661. Arndt, K.M., Ricupero-Hovasse, S., Winston, F., 1995. TBP mutants defective in activated transcription in vivo. EMBO J. 14, 1490–1497.

B.F. Pugh / Gene 255 (2000) 1–14 Auble, D.T., Hahn, S., 1993. An ATP-dependent inhibitor of TBP binding to DNA. Genes Dev. 7, 844–856. Auble, D.T., Hansen, K.E., Mueller, C.G., Lane, W.S., Thorner, J., Hahn, S., 1994. Mot1, a global repressor of RNA polymerase II transcription, inhibits TBP binding to DNA by an ATP-dependent mechanism. Genes Dev. 8, 1920–1934. Bai, Y., Perez, G.M., Beechem, J.M., Weil, P.A., 1997. Structure–function analysis of TAF130, identification and characterization of a high-affinity TATA-binding protein interaction domain in the N terminus of yeast TAF(II )130. Mol. Cell. Biol. 17, 3081–3093. Bai, Y., Salvadore, C., Chiang, Y.C., Collart, M.A., Liu, H.Y., Denis, C.L., 1999. The CCR4 and CAF1 proteins of the CCR4–NOT complex are physically and functionally separated from NOT2, NOT4, and NOT5. Mol. Cell. Biol. 19, 6642–6651. Barberis, A., Pearlberg, J., Simkovich, N., Farrell, S., Reinagel, P., Bamdad, C., Sigal, G., Ptashne, M., 1995. Contact with a component of the polymerase II holoenzyme suffices for gene activation. Cell 81, 359–368. Belotserkovskaya, R., Sterner, D.E., Deng, M., Sayre, M.H., Lieberman, P.M., Berger, S.L., 2000. Inhibition of TATA-binding protein function by SAGA subunits Spt3 and Spt8 at Gcn4-activated promoters. Mol. Cell. Biol. 20, 634–647. Birck, C., Poch, O., Romier, C., Ruff, M., Mengus, G., Lavigne, A.C., Davidson, I., Moras, D., 1998. Human TAF(II )28 and TAF(II )18 interact through a histone fold encoded by atypical evolutionary conserved motifs also found in the SPT3 family. Cell 94, 239–249. Brand, M., Leurent, C., Mallouh, V., Tora, L., Schultz, P., 1999a. Three-dimensional structures of the TAFII-containing complexes TFIID and TFTC. Science 286, 2151–2153. Brand, M., Yamamoto, K., Staub, A., Tora, L., 1999b. Identification of TATA-binding protein-free TAFII-containing complex subunits suggests a role in nucleosome acetylation and signal transduction. J. Biol. Chem. 274, 18285–18289. Burke, T.W., Kadonaga, J.T., 1997. The downstream core promoter element, DPE, is conserved from Drosophila to humans and is recognized by TAFII60 of Drosophila. Genes Dev. 11, 3020–3031. Burley, S.K., Roeder, R.G., 1996. Biochemistry and structural biology of transcription factor IID ( TFIID). Annu. Rev. Biochem. 65, 769–799. Cairns, B.R., Henry, N.L., Kornberg, R.D., 1996. TFG3/TAF30/ ANC1, a component of the yeast SWI/SNF complex that is similar to the leukemogenic proteins ENL and AF-9. Mol. Cell. Biol. 16, 3308–3316. Cang, Y., Auble, D.T., Prelich, G., 1999. A new regulatory domain on the TATA-binding protein. EMBO J. 18, 6662–6671. Chatterjee, S., Struhl, K., 1995. Connecting a promoter-bound protein to TBP bypasses the need for a transcriptional activation domain. Nature 374, 820–822. Chen, J.L., Attardi, L.D., Verrijzer, C.P., Yokomori, K., Tjian, R., 1994. Assembly of recombinant TFIID reveals differential coactivator requirements for distinct transcriptional activators. Cell 79, 93–105. Chi, T.H., Carey, M., 1996. Assembly of the isomerized TFIIA–TFIID–TATA ternary complex is necessary and sufficient for gene activation. Genes Dev. 10, 2540–2550. Chiang, C.M., Roeder, R.G., 1995. Cloning of an intrinsic human TFIID subunit that interacts with multiple transcriptional activators. Science 267, 531–536. Chicca 2nd, J.J., Auble, D.T., Pugh, B.F., 1998. Cloning and biochemical characterization of TAF-172, a human homolog of yeast Mot1. Mol. Cell. Biol. 18, 1701–1710. Coleman, R.A., Taggart, A.K., Benjamin, L.R., Pugh, B.F., 1995. Dimerization of the TATA binding protein. J. Biol. Chem. 270, 13842–13849. Coleman, R.A., Pugh, B.F., 1997. Slow dimer dissociation of the TATA binding protein dictates the kinetics of DNA binding. Proc. Natl. Acad. Sci. USA 94, 7221–7226.

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Coleman, R.A., Taggart, A.K.P., Burma, S., Chicca II, J.J., Pugh, B.F., 1999. TFIIA regulates TBP and TFIID dimers. Mol. Cell 4, 451–457. Collart, M.A., Struhl, K., 1994. NOT1(CDC39), NOT2(CDC36), NOT3 and NOT4 encode a global-negative regulator of transcription that differentially affects TATA-element utilization. Genes Dev. 8, 525–537. Collart, M.A., 1996. The NOT, SPT3 and MOT1 genes functionally interact to regulate transcription at core promoters. Mol. Cell. Biol. 16, 6668–6676. Cortes, P., Flores, O., Reinberg, D., 1992. Factors involved in specific transcription by mammalian RNA polymerase II, purification and analysis of transcription factor IIA and identification of transcription factor IIJ. Mol. Cell. Biol. 12, 413–421. Crowley, T.E., Hoey, T., Liu, J.K., Jan, Y.N., Jan, L.Y., Tjian, R., 1993. A new factor related to TATA-binding protein has highly restricted expression patterns in Drosophila. Nature 361, 557–561. DeJong, J., Bernstein, R., Roeder, R.G., 1995. Human general transcription factor TFIIA, characterization of a cDNA encoding the small subunit and requirement for basal and activated transcription. Proc. Natl. Acad. Sci. USA 92, 3313–3317. Dikstein, R., Ruppert, S., Tjian, R., 1996a. TAFII250 is a bipartite protein kinase that phosphorylates the base transcription factor RAP74. Cell 84, 781–790. Dikstein, R., Zhou, S., Tjian, R., 1996b. Human TAF 105 is a cell II type specific TFIID subunit related to hTAF 130. Cell 87, 137–146. II Dubrovskaya, V., Lavigne, A.C., Davidson, I., Acker, J., Staub, A., Tora, L., 1996. Distinct domains of hTAFII100 are required for functional interaction with transcription factor TFIIF beta (RAP30) and incorporation into the TFIID complex. EMBO J. 15, 3702–3712. Dunphy, E.L., Johnson, T., Auerbach, S.S., Wang, E.H., 2000. Requirement for TAF(II )250 acetyltransferase activity in cell cycle progression. Mol. Cell. Biol. 20, 1134–1139. Dynlacht, B.D., Weinzierl, R.O., Admon, A., Tjian, R., 1993. The dTAF 80 subunit of Drosophila TFIID contains b-transducin II repeats. Nature 363, 176–179. Eisenmann, D.M., Arndt, K.M., Ricupero, S.L., Rooney, J.W., Winston, F., 1992. SPT3 interacts with TFIID to allow normal transcription in Saccharomyces cerevisiae. Genes Dev. 6, 1319–1331. Farmer, G., Colgan, J., Nakatani, Y., Manley, J.L., Prives, C., 1996. Functional interaction between p53, the TATA-binding protein ( TBP), and TBP-associated factors in vivo. Mol. Cell. Biol. 16, 4295–4304. Farrell, S., Simkovich, N., Wu, Y., Barberis, A., Ptashne, M., 1996. Gene activation by recruitment of the RNA polymerase II holoenzyme. Genes Dev. 10, 2359–2367. Felinski, E.A., Quinn, P.G., 1999. The CREB constitutive activation domain interacts with TATA-binding protein-associated factor 110 ( TAF110) through specific hydrophobic residues in one of the three subdomains required for both activation and TAF110 binding. J. Biol. Chem. 274, 11672–11678. Gangloff, Y.G., Werten, S., Romier, C., Carre, L., Poch, O., Moras, D., Davidson, I., 2000. The human TFIID components TAF(II )135 and TAF(II )20 and the yeast SAGA components ADA1 and TAF(II )68 heterodimerize to form histone-like pairs. Mol. Cell. Biol. 20, 340–351. Gaudreau, L., Schmid, A., Blaschke, D., Ptashne, M., Horz, W., 1997. RNA polymerase II holoenzyme recruitment is sufficient to remodel chromatin at the yeast PHO5 promoter. Cell 89, 55–62. Geiger, J.H., Hahn, S., Lee, S., Sigler, P.B., 1996. Crystal structure of the yeast TFIIA/TBP/DNA complex. Science 272, 830–836. Geisberg, J.V., Struhl, K., 2000. TATA-binding protein mutants that increase transcription from enhancerless and repressed promoters in vivo. Mol. Cell. Biol. 20, 1478–1488. Georgieva, S., Kirschner, D.B., Jagla, T., Nabirochkina, E., Hanke, S., Schenkel, H.de, Lorenzo, C., Sinha, P., Jagla, K., Mechler, B.,

12

B.F. Pugh / Gene 255 (2000) 1–14

Tora, L., 2000. Two novel Drosophila TAF(II )s have homology with human TAF(II )30 and are differentially regulated during development. Mol. Cell. Biol. 20, 1639–1648. Goodrich, J.A., Hoey, T., Thut, C.J., Admon, A., Tjian, R., 1993. Drosophila TAF 40 interacts with both a VP16 activation domain II and the basal transcription factor TFIIB. Cell 75, 519–530. Goodrich, J.A., Tjian, R., 1994. TBP–TAF complexes, selectivity factors for eukaryotic transcription. Curr. Opin. Cell Biol. 6, 403–409. Goppelt, A., Stelzer, G., Lottspeich, F., Meisterernst, M., 1996. A mechanism for repression of class II gene transcription through specific binding of NC2 to TBP-promoter complexes via heterodimeric histone fold domains. EMBO J. 15, 3105–3116. Grant, P.A., Schieltz, D., Pray-Grant, M.G., Steger, D.J., Reese, J.C., Yates 3rd, J.R., Workman, J.L., 1998. A subset of TAF(II )s are integral components of the SAGA complex required for nucleosome acetylation and transcriptional stimulation. Cell 94, 45–53. Hampsey, M., 1998. Molecular genetics of the RNA polymerase II general transcriptional machinery. Microbiol. Mol. Biol. Rev. 62, 465–503. Hansen, S.K., Tjian, R., 1995. TAFs and TFIIA mediate differential utilization of the tandem Adh promoters. Cell 82, 565–575. Hansen, S.K., Takada, S., Jacobson, R.H., Lis, J.T., Tjian, R., 1997. Transcription properties of a cell type-specific TATA-binding protein, TRF. Cell 91, 71–83. Henry, N.L., Campbell, A.M., Feaver, W.J., Poon, D., Weil, P.A., Kornberg, R.D., 1994. TFIIF–TAF–RNA polymerase II connection. Genes Dev. 8, 2868–2878. Henry, R.W., Sadowski, C.L., Kobayashi, R., Hernandez, N., 1995. A TBP–TAF complex required for transcription of human snRNA genes by RNA polymerase II and III. Nature 374, 653–656. Hernandez, N., 1993. TBP, a universal eukaryotic transcription factor? Genes Dev. 7, 1291–1308. Hisatake, K., Hasegawa, S., Takada, R., Nakatani, Y., Horikoshi, M., Roeder, R.G., 1993. The p250 subunit of native TATA box-binding factor TFIID is the cell-cycle regulatory protein CCG1. Nature 362, 179–181. Hisatake, K., Ohta, T., Takada, R., Guermah, M., Horikoshi, M., Nakatani, Y., Roeder, R.G., 1995. Evolutionary conservation of human TATA-binding-polypeptide-associated factors TAFII31 and TAFII80 and interactions of TAFII80 with other TAFs and with general transcription factors. Proc. Natl. Acad. Sci. USA 92, 8195–8199. Hoey, T., Weinzierl, R.O., Gill, G., Chen, J.L., Dynlacht, B.D., Tjian, R., 1993. Molecular cloning and functional analysis of Drosophila TAF110 reveal properties expected of coactivators. Cell 72, 247–260. Hoffmann, A., Roeder, R.G., 1996. Cloning and characterization of human TAF20/15. Multiple interactions suggest a central role in TFIID complex formation. J. Biol. Chem. 271, 18194–18202. Hoffmann, A., Chiang, C.M., Oelgeschlager, T., Xie, X.L., Burley, S.K., Nakatani, Y., Roeder, R.G., 1996. A histone octamer-like structure within TFIID. Nature 380, 356–359. Holmes, M.C., Tjian, R., 2000. Promoter-selective properties of the TBP-related factor TRF1. Science 288, 867–870. Holstege, F.C.P., Jennings, E.G., Wyrick, J.J., Lee, T.I., Hengartner, C.J., Green, M.R., Golub, T.R., Lander, E.S., Young, R.A., 1998. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95, 717–728. Ikeda, K., Halle, J.P., Stelzer, G., Meisterernst, M., Kawakami, K., 1998. Involvement of negative cofactor NC2 in active repression by zinc finger-homeodomain transcription factor AREB6. Mol. Cell. Biol. 18, 10–18. Imhof, A., Yang, X.J., Ogryzko, V.V., Nakatani, Y., Wolffe, A.P., Ge, H., 1997. Acetylation of general transcription factors by histone acetyltransferases. Curr Biol. 7, 689–692. Inostroza, J.A., Mermelstein, F.H., Ha, I., Lane, W.S., Reinberg, D.,

1992. Dr1, a TATA-binding protein-associated phosphoprotein and inhibitor of class II gene transcription. Cell 70, 477–489. Jackson-Fisher, A.J., Chitikila, C., Mitra, M., Pugh, B.F., 1999. A role for TBP dimerization in preventing unregulated gene expression. Mol. Cell 3, 717–727. Jacobson, R.H., Ladurner, A.G., King, D.S., Tjian, R., 2000. Structure and function of a human TAF(II )250 double bromodomain module. Science 288, 1422–1425. Jacq, X., Brou, C., Lutz, Y., Davidson, I., Chambon, P., Tora, L., 1994. Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor. Cell 79, 107–117. John, S., Howe, L., Tafrov, S.T., Grant, P.A., Sternglanz, R., Workman, J.L., 2000. The Something About Silencing protein, Sas3, is the catalytic subunit of NuA3, a yTAF(II )30-containing HAT complex that interacts with the Spt16 subunit of the yeast CP (Cdc68/Pob3)–FACT complex. Genes Dev. 14, 1196–1208. Kassavetis, G.A., Joazeiro, C.A., Pisano, M., Geiduschek, E.P., Colbert, T., Hahn, S., Blanco, J.A., 1992. The role of the TATAbinding protein in the assembly and function of the multisubunit yeast RNA polymerase III transcription factor, TFIIIB. Cell 71, 1055–1064. Kaufmann, J., Ahrens, K., Koop, R., Smale, S.T., Muller, R., 1998. CIF150, a human cofactor for transcription factor IID-dependent initiator function. Mol. Cell. Biol. 18, 233–239. Keaveney, M., Struhl, K., 1998. Activator-mediated recruitment of the RNA polymerase II machinery is the predominant mechanism for transcriptional activation in yeast. Mol. Cell 1, 917–924. Kim, J.L., Nikolov, D.B., Burley, S.K., 1993a. Co-crystal structure of TBP recognizing the minor groove of a TATA element. Nature 365, 520–527. Kim, Y., Geiger, J.H., Hahn, S., Sigler, P.B., 1993b. Crystal structure of a yeast TBP/TATA-box complex. Nature 365, 512–520. Klages, N., Strubin, M., 1995. Stimulation of RNA polymerase II transcription initiation by recruitment of TBP in vivo. Nature 374, 822–823. Klebanow, E.R., Poon, D., Zhou, S., Weil, P.A., 1996. Isolation and characterization of TAF25, an essential yeast gene that encodes an RNA polymerase II-specific TATA-binding protein-associated factor. J. Biol. Chem. 271, 13706–13715. Klemm, R.D., Goodrich, J.A., Zhou, S., Tjian, R., 1995. Molecular cloning and expression of the 32-kDa subunit of human TFIID reveals interactions with VP16 and TFIIB that mediate transcriptional activation. Proc. Natl. Acad. Sci. USA 92, 5788–5792. Kobayashi, N., Boyer, T.G., Berk, A.J., 1995. A class of activation domains interacts directly with TFIIA and stimulates TFIIA–TFIID–promoter complex assembly. Mol. Cell. Biol. 15, 6465–6473. Kokubo, T., Gong, D.W., Yamashita, S., Horikoshi, M., Roeder, R.G., Nakatani, Y., 1993a. Drosophila 230-kD TFIID subunit, a functional homolog of the human cell cycle gene product, negatively regulates DNA binding of the TATA box-binding subunit of TFIID. Genes Dev. 7, 1033–1046. Kokubo, T., Gong, D.W., Yamashita, S., Takada, R., Roeder, R.G., Horikoshi, M., Nakatani, Y., 1993b. Molecular cloning, expression, and characterization of the Drosophila 85-kilodalton TFIID subunit. Mol. Cell. Biol. 13, 7859–7863. Kokubo, T., Gong, D.W., Wootton, J.C., Horikoshi, M., Roeder, R.G., Nakatani, Y., 1994. Molecular cloning of Drosophila TFIID subunits. Nature 367, 484–487. Kokubo, T., Swanson, M.J., Nishikawa, J.I., Hinnebusch, A.G., Nakatani, Y., 1998. The yeast TAF145 inhibitory domain and TFIIA competitively bind to TATA-binding protein. Mol. Cell. Biol. 18, 1003–1012. Kuras, L., Struhl, K., 1999. Binding of TBP to promoters in vivo is stimulated by activators and requires Pol II holoenzyme. Nature 399, 609–613. Kuras, L., Kosa, P., Mencia, M., Struhl, K., 2000. TAF-containing

B.F. Pugh / Gene 255 (2000) 1–14 and TAF-independent forms of transcriptionally active TBP in vivo. Science 288, 1244–1248. Lavigne, A.C., Mengus, G., May, M., Dubrovskaya, V., Tora, L., Chambon, P., Davidson, I., 1996. Multiple interactions between hTAFII55 and other TFIID subunits. Requirements for the formation of stable ternary complexes between hTAFII55 and the TATAbinding protein. J. Biol. Chem. 271, 19774–19780. Lavigne, A.C., Mengus, G., Gangloff, Y.G., Wurtz, J.M., Davidson, I., 1999. Human TAF(II )55 interacts with the vitamin D(3) and thyroid hormone receptors and with derivatives of the retinoid X receptor that have altered transactivation properties. Mol. Cell. Biol. 19, 5486–5494. Lee, T.I., Young, R.A., 1998. Regulation of gene expression by TBPassociated proteins. Genes Dev. 12, 1398–1408. Lee, T.I., Wyrick, J.J., Koh, S.S., Jennings, E.G., Gadbois, E.L., Young, R.A., 1998. Interplay of positive and negative regulators in transcription initiation by RNA polymerase II holoenzyme. Mol. Cell. Biol. 18, 4455–4462. Lee, T.I., Causton, H.C., Hostege, F.C., Shen, W.C., Hannett, N., Jennings, E.G., Winston, F., Green, M.R., Young, R.A., 2000. Redundant roles for the TFIID and SAGA complexes in global transcription. Nature 405, 701–704. Li, X.-Y., Virbasius, A., Zhu, X., Green, M., 1999. Enhancement of TBP binding by activators and general transcription factors. Nature 399, 605–609. Li, X.Y., Bhaumik, S.R., Green, M.R., 2000. Distinct classes of yeast promoters revealed by differential TAF recruitment. Science 288, 1242–1244. Liu, D., Ishima, R., Tong, K.I., Bagby, S., Kokubo, T., Muhandiram, D.R., Kay, L.E., Nakatani, Y., Ikura, M., 1998a. Solution structure of a TBP–TAF(II )230 complex, protein mimicry of the minor groove surface of the TATA box unwound by TBP. Cell 94, 573–583. Liu, H.Y., Badarinarayana, V., Audino, D.C., Rappsilber, J., Mann, M., Denis, C.L., 1998b. The NOT proteins are part of the CCR4 transcriptional complex and affect gene expression both positively and negatively. EMBO J. 17, 1096–1106. Lu, H., Levine, A.J., 1995. Human TAFII31 protein is a transcriptional coactivator of the p53 protein. Proc. Natl. Acad. Sci. USA 92, 5154–5158. Maldonado, E., 1999. Transcriptional functions of a new mammalian TATA-binding protein-related factor. J. Biol. Chem. 274, 12963–12966. Martinez, E., Ge, H., Tao, Y., Yuan, C.X., Palhan, V., Roeder, R.G., 1998a. Novel cofactors and TFIIA mediate functional core promoter selectivity by the human TAFII150-containing TFIID complex. Mol. Cell. Biol. 18, 6571–6583. Martinez, E., Kundu, T.K., Fu, J., Roeder, R.G., 1998b. A human SPT3–TAFII31–GCN5-L acetylase complex distinct from transcription factor IID. J. Biol. Chem. 273, 23781–23785. Matangkasombut, O., Buratowski, R.M., Swilling, N.W., Buratowski, S., 2000. Bromodomain factor 1 corresponds to a missing piece of yeast TFIID. Genes Dev. 14, 951–962. May, M., Mengus, G., Lavigne, A.C., Chambon, P., Davidson, I., 1996. Human TAF(II28) promotes transcriptional stimulation by activation function 2 of the retinoid X receptors. EMBO J. 15, 3093–3104. Mazzarelli, J.M., Atkins, G.B., Geisberg, J.V., Ricciardi, R.P., 1995. The viral oncoproteins Ad5 E1A, HPV16 E7 and SV40 TAg bind a common region of the TBP-associated factor-110. Oncogene 11, 1859–1864. Mengus, G., May, M., Jacq, X., Staub, A., Tora, L., Chambon, P., Davidson, I., 1995. Cloning and characterization of hTAFII18, hTAFII20 and hTAFII28, three subunits of the human transcription factor TFIID. EMBO J. 14, 1520–1531. Mengus, G., May, M., Carre, L., Chambon, P., Davidson, I., 1997. Human TAF(II )135 potentiates transcriptional activation by the

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AF-2s of the retinoic acid, vitamin D3, and thyroid hormone receptors in mammalian cells. Genes Dev. 11, 1381–1395. Mengus, G., Gangloff, Y.G., Carre, L., Lavigne, A.C., Davidson, I., 2000. The human transcription factor IID subunit human TATAbinding protein-associated factor 28 interacts in a ligand-reversible manner with the vitamin D(3) and thyroid hormone receptors. J. Biol. Chem. 275, 10064–10071. Mizzen, C.A., Yang, X.J., Kokubo, T., Brownell, J.E., Bannister, A.J., Owen-Hughes, T., Workman, J., Wang, L., Berger, S.L., Kouzarides, T., Nakatani, Y., Allis, C.D., 1996. The TAF(II )250 subunit of TFIID has histone acetyltransferase activity. Cell 87, 1261–1270. Moore, P.A., Ozer, J., Salunek, M., Jan, G., Zerby, D., Campbell, S., Lieberman, P.M., 1999. A human TATA binding protein-related protein with altered DNA binding specificity inhibits transcription from multiple promoters and activators. Mol. Cell. Biol. 19, 7610–7620. Moqtaderi, Z., Bai, Y., Poon, D., Weil, P.A., Struhl, K., 1996a. TBPassociated factors are not generally required for transcriptional activation in yeast. Nature 383, 188–191. Moqtaderi, Z., Yale, J.D., Struhl, K., Buratowski, S., 1996b. Yeast homologues of higher eukaryotic TFIID subunits. Proc. Natl. Acad. Sci. USA 93, 14654–14658. Muldrow, T.A., Campbell, A.M., Weil, P.A., Auble, D.T., 1999. MOT1 can activate basal transcription in vitro by regulating the distribution of TATA binding protein between promoter and nonpromoter sites. Mol. Cell. Biol. 19, 2835–2845. Nikolov, D.B., Hu, S.H., Lin, J., Gasch, A., Hoffmann, A., Horikoshi, M., Chua, N.H., Roeder, R.G., Burley, S.K., 1992. Crystal structure of TFIID TATA-box binding protein. Nature 360, 40–46. Nikolov, D.B., Burley, S.K., 1994a. 2.1 A resolution refined structure of a TATA box-binding protein ( TBP). Nat. Struct. Biol. 1, 621–637. Nikolov, D.B., Burley, S.K., 1994b. 2.1 A resolution refined structure of a TATA box-binding protein ( TBP). Nat. Struct. Biol. 1, 621–637. Nikolov, D.B., Chen, H., Halay, E.D., Usheva, A.A., Hisatake, K., Lee, D.K., Roeder, R.G., Burley, S.K., 1995. Crystal structure of a TFIIB–TBP–TATA-element ternary complex. Nature 377, 119–128. Oberholzer, U., Collart, M.A., 1999. In vitro transcription of a TATAless promoter, negative regulation by the Not1 protein. Biol. Chem. 380, 1365–1370. Ogryzko, V.V., Kotani, T., Zhang, X., Schlitz, R.L., Howard, T., Yang, X.J., Howard, B.H., Qin, J., Nakatani, Y., 1998. Histonelike TAFs within the PCAF histone acetylase complex. Cell 94, 35–44. Ohbayashi, T., Makino, Y., Tamura, T., 1999. Identification of a mouse TBP-like protein ( TLP) distantly related to the Drosophila TBP-related factor. Nucleic Acids Res. 27, 750–755. Orphanides, G., Lagrange, T., Reinberg, D., 1996. The general transcription factors of RNA polymerase II. Genes Dev. 10, 2657–2683. Ozer, J., Moore, P.A., Bolden, A.H., Lee, A., Rosen, C.A., Lieberman, P.M., 1994. Molecular cloning of the small (gamma) subunit of human TFIIA reveals functions critical for activated transcription. Genes Dev. 8, 2324–2335. Ozer, J., Mitsouras, K., Zerby, D., Carey, M., Lieberman, P.M., 1998. Transcription factor IIA derepresses TATA-binding protein ( TBP)associated factor inhibition of TBP–DNA binding. J. Biol. Chem. 273, 14293–14300. Ozer, J., Moore, P.A., Lieberman, P.M., 2000. A testis-specific transcription factor IIA ( TFIIAtau) stimulates TATA-binding protein–DNA binding and transcription activation. J. Biol. Chem. 275, 122–128. Poon, D., Bai, Y., Campbell, A.M., Bjorklund, S., Kim, Y.J., Zhou, S., Kornberg, R.D., Weil, P.A., 1995. Identification and characterization of a TFIID-like multiprotein complex from Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 92, 8224–8228.

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B.F. Pugh / Gene 255 (2000) 1–14

Prelich, G., 1997. Saccharomyces cerevisiae BUR6 encodes a DRAP1/ NC2alpha homolog that has both positive and negative roles in transcription in vivo. Mol. Cell. Biol. 17, 2057–2065. Pugh, B.F., Tjian, R., 1991. Transcription from a TATA-less promoter requires a multisubunit TFIID complex. Genes Dev. 5, 1935–1945. Rabenstein, M.D., Zhou, S., Lis, J.T., Tjian, R., 1999. TATA boxbinding protein ( TBP)-related factor 2 ( TRF2), a third member of the TBP family. Proc. Natl. Acad. Sci. USA 96, 4791–4796. Ray, B.L., White, C.I., Haber, J.E., 1991. The TSM1 gene of Saccharomyces cerevisiae overlaps the MAT locus. Curr. Genet. 20, 25–31. Reese, J.C., Apone, L., Walker, S.S., Griffin, L.A., Green, M.R., 1994. Yeast TAFIIs in a multisubunit complex required for activated transcription. Nature 371, 523–527. Reese, J.C., Zhang, Z., Kurpad, H., 2000. Identification of a yeast transcription factor IID subunit, TSG2/TAF48. J. Biol. Chem. 75, 17391–17398. Ruppert, S., Wang, E.H., Tjian, R., 1993. Cloning and expression of human TAFII250, a TBP-associated factor implicated in cell-cycle regulation. Nature 362, 175–179. Ruppert, S., Tjian, R., 1995. Human TAFII250 interacts with RAP74: implications for RNA polymerase II initiation. Genes Dev. 9, 2747–2755. Sanders, S.L., Weil, P.A., 2000. Identification of two novel TAF subunits of the yeast Saccharomyces cerevisiae TFIID complex. J. Biol. Chem. 275, 13895–13900. Sayre, M.H., Tschochner, H., Kornberg, R.D., 1992. Reconstitution of transcription with five purified initiation factors and RNA polymerase II from Saccharomyces cerevisiae. J. Biol. Chem. 267, 23376–23382. Sekiguchi, T., Miyata, T., Nishimoto, T., 1988. Molecular cloning of the cDNA of human X chromosomal gene (CCG1) which complements the temperature-sensitive G1 mutants, tsBN462 and ts13, of the BHK cell line. EMBO J. 7, 1683–1687. Selleck, S.B., Majors, J., 1987. Photofootprinting in vivo detects transcription-dependent changes in yeast TATA boxes. Nature 325, 173–177. Shen, W.C., Green, M.R., 1997. Yeast TAF(II )145 functions as a core promoter selectivity factor, not a general coactivator. Cell 90, 615–624. Sterner, D.E., Grant, P.A., Roberts, S.M., Duggan, L.J., Belotserkovskaya, R., Pacella, L.A., Winston, F., Workman, J.L., Berger, S.L., 1999. Functional organization of the yeast SAGA complex, distinct components involved in structural integrity, nucleosome acetylation and TATA-binding protein interaction. Mol. Cell. Biol. 19, 86–98. Sun, X., Ma, D., Sheldon, M., Yeung, K., Reinberg, D., 1994. Reconstitution of human TFIIA activity from recombinant polypeptides, a role in TFIID-mediated transcription. Genes Dev. 8, 2336–2348. Taggart, A.K., Pugh, B.F., 1996. Dimerization of TFIID when not bound to DNA. Science 272, 1331–1333. Takada, S., Lis, J.T.S.Z., Tjian, R., 2000. A TRF1:BRF complex directs Drosophila RNA Polymerase III transcription. Cell 101, 459–469. Tan, S., Hunziker, Y., Sargent, D.F., Richmond, T.J., 1996. Crystal structure of a yeast TFIIA/TBP/DNA complex. Nature 381, 127–151. Tanese, N., Saluja, D., Vassallo, M.F., Chen, J.L., Admon, A., 1996. Molecular cloning and analysis of two subunits of the human TFIID complex, hTAFII130 and hTAFII100. Proc. Natl. Acad. Sci. USA 93, 13611–13616. Tao, Y., Guermah, M., Martinez, E., Oegelschlager, T., Hasegawa, S., Takada, R., Yamamoto, T., Horikoshi, M., Roeder, R.G., 1997. Specific interactions and potential functions of human TAFII100. J. Biol. Chem. 272, 6714–6721.

Teichmann, M., Wang, Z., Martinez, E., Tjernberg, A., Zhang, D., Vollmer, F., Chait, B.T., Roeder, R.G., 1999. Human TATA-binding protein-related factor-2 (hTRF2) stably associates with hTFIIA in HeLa cells. Proc. Natl. Acad. Sci. USA 96, 13720–13725. Thut, C.J., Chen, J.L., Klemm, R., Tjian, R., 1995. p53 transcriptional activation mediated by coactivators TAF 40 and TAF 60. Science II II 267, 100–104. Upadhyaya, A.B., Lee, S.H., DeJong, J., 1999. Identification of a general transcription factor TFIIAalpha/beta homolog selectively expressed in testis. J. Biol. Chem. 274, 18040–18048. Usheva, A., Shenk, T., 1994. TATA-binding protein-independent initiation: YY1, TFIIB, and RNA polymerase II direct basal transcription on supercoiled template DNA. Cell 76, 1115–1121. Utley, R.T., Ikeda, K., Grant, P.A., Cote, J., Steger, D.J., Eberharter, A., John, S., Workman, J.L., 1998. Transcriptional activators direct histone acetyltransferase complexes to nucleosomes. Nature 394, 498–502. Verrijzer, C.P., Yokomori, K., Chen, J.L., Tjian, R., 1994. Drosophila TAF 150: similarity to yeast gene TSM-1 and specific binding to II core promoter DNA. Science 264, 933–941. Walker, S.S., Reese, J.C., Apone, L.M., Green, M.R., 1996. Transcription activation in cells lacking TAFIIS. Nature 383, 185–188. Wang, Z.X., Roeder, R.G., 1995. Structure and function of a human transcription factor TFIIIB subunit that is evolutionarily conserved and contains both TFIIB- and high-mobility-group protein 2-related domains. Proc. Natl. Acad. Sci. USA 92, 7026–7030. Weinzierl, R.O., Dynlacht, B.D., Tjian, R., 1993a. Largest subunit of Drosophila transcription factor IID directs assembly of a complex containing TBP and a coactivator. Nature 362, 511–517. Weinzierl, R.O., Ruppert, S., Dynlacht, B.D., Tanese, N., Tjian, R., 1993b. Cloning and expression of Drosophila TAFII60 and human TAFII70 reveal conserved interactions with other subunits of TFIID. EMBO J. 12, 5303–5309. Wieczorek, E., Brand, M., Jacq, X., Tora, L., 1998. Function of TAF(II )-containing complex without TBP in transcription by RNA polymerase II. Nature 393, 187–191. Wilson, C.J., Chao, D.M., Imbalzano, A.N., Schnitzler, G.R., Kingston, R.E., Young, R.A., 1996. RNA polymerase II holoenzyme contains SWI/SNF regulators involved in chromatin remodeling. Cell 84, 235–244. Xiao, H., Friesen, J.D., Lis, J.T., 1995. Recruiting TATA-binding protein to a promoter, transcriptional activation without an upstream activator. Mol. Cell. Biol. 15, 5757–5761. Xie, X., Kokubo, T., Cohen, S.L., Mirza, U.A., Hoffmann, A., Chait, B.T., Roeder, R.G., Nakatani, Y., Burley, S.K., 1996. Structural similarity between TAFs and the heterotetrameric core of the histone octamer. Nature 380, 316–322. Xie, J., Collart, M., Lemaire, M., Stelzer, G., Meisterernst, M., 2000. A single point mutation in TFIIA suppresses NC2 requirement in vivo. EMBO J. 19, 672–682. Yeung, K., Kim, S., Reinberg, D., 1997. Functional dissection of a human Dr1-DRAP1 repressor complex. Mol. Cell. Biol. 17, 36–45. Yokomori, K., Chen, J.L., Admon, A., Zhou, S., Tjian, R., 1993a. Molecular cloning and characterization of dTAF 30 and II dTAF 30b: two small subunits of Drosophila TFIID. Genes Dev. II 7, 2587–2597. Yokomori, K., Admon, A., Goodrich, J.A., Chen, J.L., Tjian, R., 1993b. Drosophila TFIIA-L is processed into two subunits that are associated with the TBP/TAF complex. Genes Dev. 7, 2235–2245. Zenzie-Gregory, B., Khachi, A., Garraway, I.P., Smale, S.T., 1993. Mechanism of initiator-mediated transcription: evidence for a functional interaction between the TATA-binding protein and DNA in the absence of a specific recognition sequence. Mol. Cell. Biol. 13, 3841–3849.