A: Protein Composition

TFIIH is primarily recruited to the promoter complex through association with TFIIE. Historically, TFIIH is a multiprotein complex consisting of 9 subunits: p89/XPB (gene defective in xeroderma pigmentosum patients complementation group B), p80/XPD (gene defective in xeroderma pigmentosum patients complementation group D), p62, p52, p44, p40/CDK7, p38/Cyclin H, p34, and p32/MATl. TFIIH has three enzymatic activities required for transcription: DNA-dependent ATPase, ATP-dependent helicase, and CTD kinase (Svejstrup et al., 1996; Hampsey, 1998; Lee and Young, 2000; Zurita and Merino, 2003). In addition to the enzymatic activities essential for transcription, some components of TFIIH (p89/XPD and p80/XPD) are'also involved in nucleotide excision repair. Functionally, TFIIH can be separated into two subcomplexes: a cyclin-activating kinase complex (CAK) and a core complex. The CAK complex, responsible for phosphorylating pol II CTD, is consisted of CDK7, Cyclin H, and MAT1. The core complex contains XPB helicase, p62, p52, p44, and p34. CAK and core TFIIH is linked by the XPD helicase, which is essential for DNA repair activity of TFIIH but serves a structural rather than an enzymatic role in transcription (Rossingnol et al., 1997; Coin et al., 1999). Mutations in either XPB or XPD lead to several human diseases, including xeroderma pigmentosum (XP), tricothiodystrophy (TTD), and Cockayne syndrome (CS; Lee and Young, 2000; Lehmann, 2001; Zurita and Merino, 2003). Recent studies have now identified a tenth subunit of TFIIH, TFB5, in yeast (Ranish et al., 2004) and humans (Giglia-Mari et al., 2004). Human TFB5 is implicated in the DNA repair syndrome TTD group A disease (Giglia-Mari et al., 2004).

B: DNA-Dependent ATPase Activity

The ATPase activity of TFIIH is required for transcription initiation and promoter clearance. Although an initial report indicated that TFIIH and ATP hydrolysis are only required for pol II promoter clearance, but not for transcription initiation and formation of the first phosphodiester bond in CpA dinucleotide-primed reactions (Goodrich and Tjian, 1994), subsequent studies found that TFIIH ATPase activity is indeed necessary for initial promoter opening and first phosphodiester bond formation when natural nucleotide substrates were used to initiate the transcription reactions (Holstege et al., 1996, 1997). In general, without TFIIH, pol II tends to stall on the promoter-proximal region, leading to abortive transcription products; the addition of TFIIH in the presence of ATP significantly reduces the amount of the promoter-stalled pol II complex, indicating a direct involvement of TFIIH in promoter clearance (Dvir et al., 1997; Kugel and Goodrich, 1998; Kumars al., 1998).

C: ATP-Dependent Helicase Activity

TFIIH contains two helicases, XPB and XPD which unwind the DNA in a 3'—» 5' and 5'—>3' direction, respectively, making TFIIH a bidirectional DNA helicase (Schaeffer et al., 1994). The XPB helicase activity is essential for promoter opening in the transcription process (Guzman and Lis, 1999). While XPB 3'—> 5' helicase activity is critical for both DNA repair and transcription, the XPD 5'—»3' helicase activity is only required for DNA repair (Zurita and Merino, 2003). The ATP-dependent DNA helicase activities of TFIIH are also necessary for opening the promoter region surrounding the transcription start site and maintaining the transcription open complex (Holstege et al., 1997). This requirement for XPB helicase activity in transcription may be bypassed by the use of either supercoiled or premelted templates (Parvin and Sharp, 1993; Pan and Greenblatt, 1994; Parvin et al., 1994; Tantin and Carey, 1994), further supporting a role of TFIIH in open complex formation.

D: TFIIH and Nucleotide Excision Repair

Nucleotide excision repair (NER) is a process where damaged DNA is removed and replaced by newly synthesized DNA based on sequence information from the intact template strand. The finding that p89/XPB is identical to ERCC3, a DNA excision repair protein which is defective in patients with xeroderma pigmentosum, led to the hypothesis that transcription might be coupled to DNA repair (Schaeffer et al., 1993). Consistent with the fact that TFIIH may play a dual role in transcription and DNA repair is the observation that transcriptionally active genes are preferentially repaired (Bohr et al., 1985; Mellon and Hanawalt, 1989). For NER, the combined helicase activities of XPB and XPD seem to be required. Experiments have shown that microinjection of TFIIH into human XPD- or XPB-mutant cells led to complementation of repair -deficient phenotype (van Vuuren et al., 1994). Similarly, yeast cells with a mutation in the yeast homolog for XPD was rescued with the addition of TFIIH and not by the addition of XPD alone, suggesting that NER is only functional in the context of TFIIH (Wang et al., 1994). Subsequent studies have shown multiple components in TFIIH are required for DNA repair, including XPB, XPD, p62, p52, and p44 (Drapkin et al., 1994; Humbert et al., 1994; Schaeffer et al., 1994; Wang et al., 1995; Jawhari et al., 2002). The XPB and XPD helicase functions are required for transcription-coupled NER, as defects in helicase activity are linked to human diseases including XP, TTD, and CS. Recent studies have unraveled the mechanism by which the XPB helicase subunit of TFIIH functions in NER and transcription. Experiments showing phosphorylation of the serine 751 residue of XPB leads to inhibition of NER activity, but does not prevent TFIIH from unwinding DNA (Coin et al., 2004). Instead, phosphorylation of XPB serine 751 prevents the 5' incision triggered by the ERCC1-XPF endonuclease (Coin et al., 2004), providing convincing evidence that a separate but essential role of TFIIH is involved in both transcription and DNA repair.

E: TFIIH and CTD Phosphorylation

CDK7 is the kinase responsible for phosphorylating the serine 5 residue of the pol II CTD, whose activity is regulated by cyclin H, MAT1, TFIIE and Mediator (Svejstrup et al., 1996). The CDK7-cyclin H-MAT1 CAK complex in the context of TFIIH has higher activity in phosphorylating the CTD compared with the free form of CAK (Yankulov and Bentley, 1997). Phosphorylation of serine 5 leads to recruitment of 5' capping enzyme (Cho et al., 1997; Komarnitsky et al., 2000; Rodriguez et al., 2000; Schroedcre? al., 2000; Pei et al., 2001) and promoter escape. That CTD phosphorylation regulates the transition from transcription initiation to elongation is supported by observations that pol II enters PIC assembly as the hypophosphorylated IIA form and escapes the promoter as the hyperphosphorylated IIO form (Hampsey, 1998). Besides phosphorylating CTD, TFIIH has also been shown to phosphorylate transcriptional activators, such as p53 (Lu et al., 1997), retinoic acid receptora (Rochette-Egly et al, 1997), retinoic acid receptory (Bastien et al., 2000), Ets-1 (Drané et al., 2004), estrogen receptora (Chen et al., 2000), and general cofactor PC4 (Kershnar et al., 1998). The CTD kinase activity of TFIIH can also be stimulated via interaction with transcriptional activators (Jones, 1997).

F: TFIIH-Activator Interactions

Many activators have been shown to interact with TFIIH including Gal4-VP16, E2F1, Rb, p53, ERa, RARa, RARy, and androgen receptor (reviewed by Zurita and Merino, 2003). Consistent with TFIIH's ability to interact with many activators is the finding that TFIIH can function as a coactivator in a reconstituted cell-free transcription system (Wu et al., 1998). Perhaps activators may work by enhancing the recruitment of TFIIH for PIC assembly or stimulating the enzymatic activities of TFIIH (Zurita and Merino, 2003). Conversely, TFIIH may covalently modify amino acid residues critical for activator function. For example, TFIIH has been shown to stimulate the transcriptional activity of the N-terminal activation domain (AF-1) of nuclear receptors RARa 1 and RARy via phosphorylation of specific serine residues in AF-1 (Rochette-Egly et al., 1997; Bastien et al., 2000). Other than functioning through the kinase activity of CDK7, mutations in the XPD subunit of TFIIH also exhibited impaired phosphorylation of RARa (Keriel et al., 2002), indicating that XPD may modulate CDK7 activity within the TFIIH complex and thereby regulate nuclear receptor phosphorylation and its transactivation activity. This finding further suggests that XPD not only participates in DNA repair but also in the transcriptional process.

PIC Assembly

A: Initiation of PIC Assembly

Formation of the PIC on the promoter is usually the rate-limiting step in transcriptional activation (Lemon and Tjian, 2000). Within eukaryotic genes, there are enhancer regions with clusters of upstream activation sequences, which allow for activator binding to regulate transcription activity. In addition to enhancers, eukaryotic genes may also contain locus control regions (LCRs) consisting of multiple transcription factor-binding sites; but unlike enhancers, which are orientation-independent and distance-independent, LCR functions are limited by position (Grosveld, 1999). Initiation of PIC formation is normally triggered by activator binding to their cognate binding sites and followed by recruitment of transcriptional coactivators or by directly contacting GTFs. A single activator may have multiple contacts with GTFs in order to regulate multiple steps of PIC formation. For example, p53 can interact with multiple GTFs, including TBP, TAFs, TFIIB, and TFIIH (Ko and Prives, 1996). These interactions may stimulate

TFIID-TFIIA-promoter complex assembly (Xing et al., 2001) or target different steps of PIC formation in a temporal manner in response to environmental stresses (Espinosa et al., 2003). Conversely, multiple activators, as in an enhanceosome complex, may work in a combinatorial manner to initiate the assembly of a transcription-competent complex (reviewed by Carey, 1998; Merika and Thanos, 2001).

B: Chromatin Barrier to PIC Assembly

An additional level of complexity must be contemplated when considering that competent PIC formation must first overcome the inherently repressive nature of chromatin. TFIID with its ability to covalently modify histones (see TFIID section) may play a critical role in modifying chromatin structure for transcription to occur. Experiments have shown that TFIID, rather than TBP, is essential for activator-dependent transcription on chromatin templates (Wu et al., 1999). In addition to TFIID, pol II holoenzyme, which also contains SWI/SNF and GCN5, is able to initiate transcription from chromatin (Wu et al., 1999), implicating an important role of chromatin-modifying activity in overcoming nucleosome-mediated repression of PIC assembly. With the advent of in vitro chromatin assembly, initially using Xenopus oocyte extracts (Glikin et al., 1984) and now with a completely defined recombinant chromatin assembly system coupled to transcription analysis (Fyodorov and Kadonaga, 2003; An and Roeder, 2004; Thomas and Chiang, 2005), the answers to many of these fascinating questions involving PIC formation on chromatin templates will be further uncovered in the near future.

C: Stepwise Recruitment vs. Pol II Holoenzyme Pathway

Evidence exists for both models of PIC assembly (Hampsey, 1998; Lemon and Tjian, 2000). The differences in factor recruitment and composition of the general transcription machinery assembled on distinct p53 target genes, in response to DNA-damaging agents (Espinosa et al., 2003), certainly argue for the existence of the sequential assembly pathway in vivo. The fact that diverse transcription complexes can be detected and isolated in vivo and in vitro further supports this model. The advantage for the stepwise assembly pathway is to selectively fine-tune individual steps for different signaling events without globally inactivating the cascade leading to gene activation. It also provides an efficient way to reactivate the pathway by simply modulating the rate-limiting step. However, a de novo assembly of functional transcription complexes may require a significant time, considering more than 40 polypeptides must be assembled correctly in a limited time frame to respond to cellular demands. Conversely, pol II holoenzymes are preformed prior to the initiation of transcription and are thus able to respond more rapidly to the transcriptional need of the cell. A major disadvantage of the holoenzyme pathway is that a distinct set of preassembled complexes must exist for different types of transcriptional events, which is economically unfavorable for cells to generate many complexes differing in peripheral components. However, multiple pol II holoenzyme complexes with different protein compositions involved in various biological processes have indeed been isolated (Lee and Young, 2000; see also the holoenzyme section). Thus, how transcription complexes are assembled in vivo on distinct activator-targeted genes and its functional implications remain to be investigated both on an individual and on a genome-wide basis.


Tremendous progress has been achieved concerning the structure and function of GTFs and pol II. TFIID is recognized as the key promoter recognition factor, while TFIIA and TFIIB stabilize TFIID binding to DNA. In addition to core promoter recognition, TFIID also functions as a coactivator in mediating interactions between activators and GTFs. It is an enzyme with multiple activities, including kinase, acetylase, and ubiquitin activating/conjugating activities. These multiple activities of TFIID on histones may aid in PIC assembly on chromatin templates. Following the assembly of TFIID-TFIIA-TFIIB on the promoter region, pol II/TFIIF, TFIIE, and TFIIH join the complex to form a PIC. The enzymatic activities inherent to TFIIH then facilitate promoter melting and the transition from initiation to elongation following initial phosphodiester bond formation. Although PIC assembly was defined biochemically in a stepwise fashion in vitro, it remains unclear whether the PIC is indeed assembled in this manner in vivo, or as a preexisting pol II holoenzyme complex, or via other undefined pathways. Regardless of which pathway operates in vivo, a common theme in gene regulation is activator-mediated recruitment of GTFs and pol II to upregulate PIC assembly. Activators may target individual GTFs, such as TFIID (Burley and Roeder, 1996; Naar et al., 2001; Wu and Chiang, 2001a), TFIIB (Roberts et al., 1993; Colgan et al., 1993; Sauer et al., 1995), TFIIE (Martin et al., 1996), TFIIF (Joliot et al., 1995; Martin et al., 1996; McEwan and Gustafsson, 1997; Reidef al., 2002),

TFIIH (Zurita and Merino, 2003), TFIIA (Ozer et al., 1994, 1998a; Kobayashi et al., 1995; Lieberman et al., 1997), and pol II (Cheong et al., 1995; Wu and Chiang, 2001a). Alternatively, activators may recruit pol II holoenzyme to the promoter via interaction with Mediator, the key component in pol II holoenzyme originally identified in yeast (Naar et al., 2001; Wu et al., 2003). Although it is generally agreed that Mediator may function as a coactivator in mediating transcriptional activation by facilitating pol II entry to the TFIID-TFIIB-promoter complex (Wu et al., 2003), whether it exists as a preassembled pol II holoenzyme complex in a cellular environment or is recruited separately to pol II by transcriptional activators remains to be further investigated.


We are grateful for Drs. Parminder Kaur, Mary C. Thomas and Shwu-Yuan Wu for their comments on this chapter. The research conducted in Dr. Chiang's laboratory is currently sponsored by grants CA103867 and GM59643 from the National Institutes of Health in the United States.


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