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A facelift for the general transcription factor TFIIA
Biochimica et Biophysica Acta 1769 (2007) 429 – 436 www.elsevier.com/locate/bbaexp
Review
A facelift for the general transcription factor TFIIA Torill Høiby a,1,2 , Huiqing Zhou a,2 , Dimitra J. Mitsiou b , Hendrik G. Stunnenberg a,⁎ a
NCMLS, Department of Molecular Biology, 191, Radboud University of Nijmegen, PO Box 91001, 6500 HB Nijmegen, The Netherlands Molecular Endocrinology Program, Institute of Biological Research and Biotechnology, The National Hellenic Research Foundation, 48Vas. Constantinou Av, 11635 Athens, Greece
b
Received 7 February 2007; received in revised form 20 April 2007; accepted 24 April 2007 Available online 5 May 2007
Abstract TFIIA was classified as a general transcription factor when it was first identified. Since then it has been debated to what extent it can actually be regarded as “general”. The most notable feature of TFIIA is the proteolytical cleavage of the TFIIAαβ into a TFIIAα and TFIIAβ moiety which has long remained a mystery. Recent studies have showed that TFIIA is cleaved by Taspase1 which was initially identified as the protease for the proto-oncogene MLL. Cleavage of TFIIA does not appear to serve as a step required for its activation as the uncleaved TFIIA in the Taspase1 knock-outs adequately support bulk transcription. Instead, cleavage of TFIIA seems to affect its turn-over and may be a part of an intricate degradation mechanism that allows fine-tuning of cellular levels of TFIIA. Cleavage might also be responsible for switching transcription program as the uncleaved and cleaved TFIIA might have distinct promoter specificity during development and differentiation. This review will focus on functional characteristics of TFIIA and discuss novel insights in the role of this elusive transcription factor. © 2007 Elsevier B.V. All rights reserved. Keywords: TFIIA; Transcription; Taspase1; Cleavage
1. Introduction One of the groundbreaking discoveries in eukaryotic transcription was the identification of nuclear RNA polymerase (Pol) I, II and III that transcribe large ribosomal genes, protein coding and some small nuclear RNA genes, and most small structural RNA genes, respectively [1–3]. The complexity and variability of the general transcription machinery in Eukarya was further extended through the discovery of specific accessory factors [4–7]. The inability of RNA polymerases to initiate transcription by themselves provided the basis for characterising the general transcription factors (GTFs) that reconstitute accurate transcription initiation; for RNA Pol II, they include TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH [8– 11]. Subsequent research has unveiled a multitude of additional (co-)activators, (co-)repressors and multi-protein complexes ⁎ Corresponding author. Tel.: +31 24 3610524; fax: +31 24 3610520. E-mail address: [email protected] (H.G. Stunnenberg). 1 Present address: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. 2 These authors contribute equally to this work. 0167-4781/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbaexp.2007.04.008
that mediate communication between DNA-bound transcription factors and the general transcription machinery. In addition the general transcription machinery itself varies considerably. The role of the general transcription factor TFIIA has been particularly elusive. In initial studies the TFIIA-containing fraction was necessary to reconstitute basal transcription in vitro [12]. Consequently, TFIIA was classified as a general transcription factor, which was later debated because of contradicting results as to its role in transcription. Recent data suggest that promoters vary widely in their requirement for TFIIA for transcriptional activation, and it appears that TFIIA may not be generally involved in transcription but may possess promoter-specificity during development and differentiation. This review will discuss TFIIA from a transcriptional point of view with an emphasis on its proteolytical cleavage by Taspase1, its regulation and consequences thereof. 2. The role of TFIIA in general transcription Functional and biochemical studies have concluded differently as to the role TFIIA in transcription, and TFIIA has been described as essential [13,14], stimulatory [8] or dispensable
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[15,16]. These inconsistencies are generally believed to originate from the impurities in the factors/fractions used in the respective in vitro transcription studies. TFIIA has been shown to stimulate transcription by stabilizing TBP binding to the TATA box [17] and by regulating TBP or TFIID dimerization to accelerate DNA binding. However, it does not appear to stimulate TBP-mediated transcription from a core promoter when using highly purified factors [18–21]. In complementation assays using partially purified factors, TFIIA has a stimulatory effect, presumably by reversing the inhibitory effects of negative co-factors like NC1, Dr1/NC2, Dr2/Topo1, HMG1 and DSP1, as well as by counteracting the effects of BTAF1 and TAF1 [18,22–29]. TFIIA is crucial for basal and activated transcription from TATA-less promoters in vitro, suggesting that it has a core promoter-specific role beyond stabilizing TBP binding to DNA [30]. Furthermore, TFIIA functions as a co-activator for several activators (AP-1, Gal4AH, Zta, VP16, CTF, NTF, Sp1) [18,19,31–33] and enhances the effect of co-activators like PC4 and HMG2 [20,34]. Additionally, some studies have implied TFIIA in RNA Pol III transcription, for example on the 5S and U6 RNA promoters [35,36], whereas this has been contradicted by other results [37–39]. Various approaches have been employed to study the function of TFIIA in vivo e.g. by disrupting the TBP–TFIIA–DNA interaction. Stargell and Struhl employed a yeast TBP mutant impaired in its interaction with TFIIA and demonstrated a specific impairment in the response to acidic activators, whereas bulk RNA Pol II transcription was unaffected [40]. Selective transcriptional effects and a partial inhibition of cell-cycle progression [41] have been observed by Ozer et al. upon diminishing the interactions between TFIIA and TBP. Subsequent studies have shown that a ten times depletion of TFIIA leads to a moderate decrease in RNA Pol II transcription from both TATA-containing and TATA-less promoters [38] and a wide variety of genes is affected minimally (2–3 fold) when TFIIA is reduced to less than 1% of the wild-type level [37]. These mild effects are in contrast to the depletion of general transcription factors like TBP, TFIIB, TFIIH subunits and RNA Pol II subunits which leads to a total elimination of RNA Pol II transcription in yeast [37]. However, TFIIA depleted cells do arrest specifically at G2/M arguing that TFIIA has an important role in controlling genes related to cell cycle progression. The moderate effects on transcription upon TFIIA depletion could be explained by Mot1 functionally replacing TFIIA in preinitiation complexes, as shown in yeast studies by Geisberg and Struhl where Mot1 co-occupies promoters with TBP, TFIIB and Pol II after stress [42]. This hypothesis is supported by the observation that Mot1 can assist in recruiting TBP to promoters during gene activation, much in the same way TFIIA is thought to do [43,44]. One unifying explanation would be that TFIIA acts more like a co-activator than as a general factor. In support of this hypothesis, TFIIA has been reported to interact, either physically or genetically, with a number of factors (summarised in Table 1), including general transcription factors like TFIID or SAGA components as well as repressors. These observations support a model in which TFIIA functions by communicating
between activators and the general transcription machinery, modulating the activities of the TFIID and SAGA components, and counterbalancing the effect of repressors. Based on its coactivating characteristics and association with TBP, TFIIA has also been proposed to be a TBP-associated factor (TAF) that dissociates from the TFIID complex more readily than the other TAFs [47]. This model is in agreement with the identification of the TBP–TFIIA containing Complex (TAC) consisting of TBP and TFIIA but no classical TAFs. To classify TFIIA as a TAF may, however, also be inappropriate; recent in vivo studies in yeast have shown that the TBP/TAF ratio varies significantly amongst different promoters in contrast to the TBP/TFIIA ratio [63]. This suggests that some TFIIA-dependent genes are TAFindependent, whereas others are TAF-dependent. 3. The architecture of the TFIIA and its paralogue ALF Budding yeast (S. cerevisiae) TFIIA was originally purified as a complex consisting of two polypeptides with molecular masses of 32 and 13.5 kDa [64] encoded by TOA1 and TOA2, that are both essential in yeast [13]. In contrast, TFIIA was found to be composed of three polypeptides, α, β and γ, in Homo sapiens and Drosophila melanogaster [18,51,65]. Cloning of TFIIA revealed that the two larger subunits, α and β, are encoded by a single gene and post-translationally processed. TFIIAαβ and TFIIAγ in higher eukaryotes are the respective homologues of the yeast subunits TOA1 and TOA2 [18,51,65] (Fig. 1). The crystal structure of yeast TFIIA/TBP/DNA complex revealed that the two yeast TFIIA subunits are intimately associated in two domains: a six-stranded β-sandwich domain that is composed of two β-sheets and a left-handed four-helix bundle Table 1 TFIIA-interacting proteins Factor
Function
Reference
AP-1 Zta VP16 CTF NTF SP1 GAL4 PC4 HMG2 scTAF11 dmTAF4 TBP TRF2 CREM GCN5 SWI2 NHP6 TAF1 BTAF1 NC2 HMGB1 RBP SPT3 SPT8
Activator of transcription Activator of transcription Activator of transcription Activator of transcription Activator of transcription Activator of transcription Activator of transcription Co-activator of transcription Co-activator of transcription TBP-associated factor TBP-associated factor TATA-binding protein TBP-related factor 2 Activator of transcription in germ cells Histone acetylase, component of SAGA Chromatin remodeling Architectural gene modulation TBP-associated factor Repressor of transcription Repressor of transcription Repressor of transcription Repressor of transcription Component of SAGA Component of SAGA
[45] [19,45,46] [45–47] [45] [31] [31] [45,48] [49] [34] [50] [51] [50–53] [54] [55] [56] [56] [56] [25,27,29] [44] [57,58] [59] [60] [61] [62]
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Fig. 1. Structural comparison of S. cerevisiae TFIIA (TOA1 and TOA2), human TFIIA (hTFIIAαβ and hTFIIAγ) and human ALF. The four-helix bundle (FHB) domain and the β-barrel domain identified in the crystal studies as well as the spacer domain, the acidic domain and the Cleavage Recognition Site (CRS) are indicated.
domain. The β-sandwich domain interacts with the N-terminal stirrup region of TBP and with the backbone of the TATA box whereas the four-helix bundle projects away from the TFIIA/ TBP/DNA complex and is available for additional interactions with transcription factors [66,67]. Interaction of TFIIA with TBP and DNA places TFIIA immediately upstream of the TATA box on the opposite side of DNA from TFIIB [66–68], indicating the role of TFIIA in the preinitiation complex. Comparison of the crystal structure between the human and yeast TFIIA/TBP/DNA complex revealed conserved architecture [69]. The high sequence and structural conservation of TFIIA from yeast to human underlines the significance of TFIIA in fundamental aspects of eukaryotic transcription. The highly conserved N- and C-terminal domains of TOA1 are essential but a significant portion of the non-conserved middle region can be removed without loss of viability in yeast. In contrast, introducing the human acidic region or the very C-terminal region of TFIIAαβ into TOA1 has severe effects on yeast growth [38]. Thus, despite the overall conservation, some protein properties are not conserved across species [70], although it is not clear what the functions of these domains are. The general transcription factors were long believed to be unique and essential for transcription of all RNA Pol II promoters. This view was challenged by the discovery of cell- and tissuespecific paralogues in higher eukaryotes of two of the general transcription factors. Hitherto, paralogues have only been identified for TBP and TFIIA, whereas RNA Pol II, TFIIB, TFIIE, TFIIF and TFIIH are all present as a single gene in the D. melanogaster, Caenorhabditis elegans and mammalian genomes. TBP is in fact supplemented with at least three paralogues in metozoans; the insect-specific TRF1 [71–73], the TLF/TRF2 which is found in all metozoan genomes examined thus far [74– 78] and the vertebrate TBP2 [79,80]. TFIIA turned out to have
one paralogue, the TFIIA-Like Factor (ALF) [81–84], which is also subject to proteolytic cleavage [85,86]. Expression patterns of TFIIA, ALF, TBP paralogues and TAF variants revealed that transcription during gametogenesis and early embryogenesis could be regulated by diverse developmental and cell typespecific transcription factor complexes. For example in both Xenopus and mice, ALF and TBP2 are specifically coexpressed in oocytes, and their expression levels are reduced during fertilization; in contrast, their somatic counterparts TFIIAαβ and TBP transcripts are present in somatic cells as well as reproductive tissues [87,88]. In Xenopus and mammalian cells, only one TFIIAγ subunit has been identified so far, indicating that TFIIAγ interacts with both TFIIAαβ and ALF to form a heterodimeric complex that stabilizes binding of TBP to promoter DNA. Interestingly, rice has shown to have two TFIIAγ-like genes, TFIIAγ1 and Xa5 (TFIIAγ5). Xa5/xa5, a V39E substitution variant of TFIIAγ1, was functionally confirmed to confer resistance to rice bacterial blight, suggesting that duplication of the TFIIAγ gene gives rise to a new function for disease resistance during evolution [89]. An archeal homologue of TFIIA is missing [90], which may mean that TFIIA has evolved in organisms that require a more elaborate regulation of transcriptional activation. 4. Cleavage of TFIIA by Taspase1 In initial studies, the uncleaved TFIIAαβ was not detected in cell extracts, which led to the assumption that cleavage of TFIIA occurs directly after or during translation, and the cleaved TFIIA was seen as the functional form [19,65]. Years later this point of view had to be reconsidered because studies in P19 embryonal carcinoma (EC) cells revealed considerable levels of the uncleaved form of TFIIAαβ which was shown to be transcriptionally active. In P19 EC and other embryonal cells,
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the uncleaved form of TFIIA interacts stably with TBP in a TAFfree complex termed TAC [91]. TAC formation is stimulated by the co-activator p300 in EC cells, and over-expression of p300 appears to facilitate formation of TAC also in other cells [92]. These observations provided the first hint that cleavage of TFIIAαβ is a regulated event that may be linked to the differentiation state of cells, and motivated renewed efforts to identify the TFIIA cleavage site and the protease(s) involved. The mapping and characterisation of the human TFIIA cleavage site led to the delineation of the cleavage recognition sequence (CRS), a string of four residues (272–275) that are essential for TFIIA cleavage [85]. The importance of the CRS was underscored by its strict conservation amongst higher eukaryotes (Fig. 2). The identification of the protease responsible for TFIIA cleavage was greatly helped by the observation that the CRS of TFIIA is identical to the protease cleavage site of the protooncogene Mixed-Lineage Leukemia (MLL) [93], and consistent with that, MLL and TFIIA were shown to be cleaved by the same protease, Taspase1 [94,95]. Taspase1 cleaves human TFIIA at D274/G275 within the highly conserved CRS [95]. In line with this observation, studies on the TFIIA-like factor (ALF) indicate that the cleavage site of ALF is at D341/G342, corresponding to D274/G275 in human TFIIA [86]. From an evolutionary point of view, the cleavage process appears to have evolved subsequent to the divergence of S. cerevisiae where TFIIA does not have a CRS and consistently, a Taspase1 like L-asparaginase is absent. In contrast, the TFIIA of fission yeast (Schizosaccharomyces pombe), A. thaliana and C. elegans all contain a CRS (Fig. 2) and their genomes encode a Taspase1-like factor (Hoiby and Stunnenberg, unpublished data). It is therefore conceivable that TFIIA undergoes cleavage in these organisms, suggesting that cleavage plays a role in TFIIA regulation and function in higher organisms beyond S. cerevisiae.
Fig. 2. Alignment of the CRS and the cleavage site of TFIIA and MLL from different organisms, H. sapiens (h), Mus musculus (m), X. laevis (x), D. melanogaster (d), C. elegans (e), Arabidopsis thaliana (a), S. pombe (sp) and Takifugu rubripes (r). The conserved CRS is boxed. Cleavage of TFIIA and MLL by Taspase1 is at D/G, indicated with an arrow. D278 marked with ⋄ is the identified Nterminal end of the β subunit of TFIIA purified from mammalian cells.
5. Regulation of cleavage In contrast to earlier reports that the uncleaved TFIIA was not detectable in crude cell extracts, it has been detected in all cell lines investigated so far when cell extracts are fractionated through a Ni-NTA column. The abundance of the uncleaved TFIIA appears to vary in different cell lines, with P19 EC cells hitherto showing the highest ratio of uncleaved to cleaved TFIIA. Whether regulation of TFIIA cleavage occurs by regulation of the Taspase1 activity or by post-translational modification of TFIIA that interferes with cleavage remains to be investigated. One such modification may well be phosphorylation, since mimicking phosphorylation by the mutation T276D adjacent to the CRS renders TFIIA uncleavable, whereas mutant T276A behaves like wild-type TFIIA ([85] and Høiby, T. and Stunnenberg, H.G., unpublished data). Furthermore, putative phosphorylation sites (T276, T279, S280, S281) close to the CRS seem to affect TFIIA stability [85], and their potential kinase casein kinase II (CKII) has been implicated in promoter selection and in the regulation of a number of transcription factors [96–98]. In addition to phosphorylation, acetylation is another modification that might affect cleavage of TFIIA because the stimulatory role of p300 in TAC formation is dependent on its HAT activity, and consistently, the uncleaved form of TFIIAαβ is preferentially acetylated [92]. The exact role of p300 in regulation of TFIIA cleavage can at present only be speculated upon, but it may affect the efficacy of cleavage, either directly or by modulating the Taspase1 activity. 6. The function of TFIIA cleavage Until the recent efforts to investigate the cleavage site of TFIIA and its function, the general view was that cleavage renders TFIIA transcriptionally active. Our studies have shown that inhibition of cleavage through a single mutation in the CRS such as G275A significantly prolonged the half-life of TFIIA [85]. Cleaved TFIIAα and -β but not uncleaved TFIIAαβ are substrates for proteasomal degradation, indicating that the level of TFIIA is regulated by cleavage. These observations lead to a new concept that the function of cleavage may be to initiate a TFIIA degradation pathway which could be directly or indirectly linked to transcription. Several reports conclude that cellular TFIIA levels fluctuate; for example, TFIIA expression declines dramatically upon HSV virus infection, which suggests that regulation of TFIIA levels is part of a cellular program enabling the transition from early to late viral gene transcription during infection, and implies a requirement for TFIIA in transcription of early but not late genes [99]. Furthermore, inactivation of TFIIA during terminal differentiation of avian erythroid cells correlates to a general repression of gene activity in these cells [100], and TFIIAγ expression is up-regulated during Ras-mediated photoreceptor induction in D. melanogaster [101]. Collectively, these results suggest that regulation of cellular TFIIA levels contributes to the regulation of gene expression during processes such as cell differentiation and transformation. Regulating TFIIA stability and TFIIA cleavage seems to be one way to achieve this.
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Initially, the N-terminus of the human TFIIAβ subunit was identified as D278 [85] by sequencing the β subunit purified from FM3A cells stably expressing human TFIIAαβ. However, N-terminal sequencing of in vitro Taspase1-cleaved TFIIA revealed that its cleavage site was between D274/G275 which is identical to the cleavage site determined for MLL [95] and 3 amino acids upstream of the previously identified N-terminus (Fig. 2). The apparent inconsistency may be the result of a secondary cleavage in vivo by either an endo- or an exopeptidase activity. Such a secondary cleavage would generate a potential N-terminal degron in TFIIA, D278, and TFIIA cleavage could thus be a step of the N-end rule destruction pathway to regulate the level and transcriptional activity of TFIIA. Interestingly, studies in embryonal P19 cells unexpectedly showed that the uncleaved TFIIA interacts with TBP and participates in a transcriptionally competent complex, TAC [91]. This study raised the question whether the uncleaved and cleaved TFIIA have distinct target genes and whether cleavage may be critical for changing specific transcription programs and hence play a role in differentiation and development. The uncleaved TFIIA and TAC were hypothesized to be components of the transcription machinery specific for embryonic development, whereas cleaved TFIIA could be involved in TFIID-mediated transcription for general promoters (Fig. 3). Recently, this new model has been modified once again based on emerging data. The protease for TFIIA cleavage, Taspase1, has been knocked-out in the mouse model, and Taspase1−/− MEF cells in which only uncleaved TFIIA was detected could be established [95]. Taspase1 knock-out mice survived till birth and showed minor overall defects [102], indicating that the uncleaved form of TFIIA is functional. In Xenopus, an uncleavable TFIIA mutant (G269A, corresponding to G275A in human) was able to rescue TFIIA knock-down embryos in both development and gene expression [95], which is in full agreement with a model in which the uncleaved form of TFIIA is transcriptionally active in early embryogenesis and sufficient
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for bulk transcription. Whether the functional uncleaved TFIIA is in the TAC complex or plays its transcriptional role via the TFIID complex is yet to be determined. It is possible that in early developmental stages, uncleaved TFIIA is sufficient for transcription, and at later stages cleavage of TFIIA is important for expression of a subset of genes. Recent data from Taspase1−/− MEFs showed that these cells in which TFIIA remains uncleaved exhibit cell cycle defects, indicating that uncleaved substrate(s) of Taspase1 is (are) responsible for these defects. TFIIA, one of the substrates identified thus far, was previously shown to be important for cell cycle progression [41]; therefore, it will be interesting to test whether the cleaved TFIIA is involved in cell cycle control (Fig. 3). 7. Perspectives Over the past 20 years, TFIIA has transformed from a rather inconspicuous protein that plays a role in transcription in a vaguely described manner to a transcription factor that appears to be tightly regulated with a particular role in differentiation and development. The presence of the CRS and the corresponding Taspase1-like protease recognizing the CRS indicates that cleavage of TFIIA has evolved subsequent to the divergence of S. cerevisiae, allowing a more delicate transcriptional control in higher organisms. The observation that the uncleaved TFIIA is sufficient for bulk transcription in early embryogenesis raises questions as to the particular function of cleavage and of the cleaved form itself which represents the vast majority of TFIIA in most differentiated cells. The cleaved form may play a specific transcriptional role regulating a subset of genes like cell cyclerelated genes at later developmental stages and/or it may be involved in bulk transcription and partially overlap with the function of the uncleaved TFIIA (Fig. 3). The cleaved TFIIA may also be a transient by-product of a transcriptionally linked cleavage process that is about to be degraded (Fig. 3). A
Fig. 3. Model for function of TFIIA. Uncleaved TFIIAαβ/γ can assemble with TBP into TAC and this is facilitated, directly or indirectly, by p300. TAC is responsible for the transcriptional activation of hitherto unknown embryo-specific promoters. Uncleaved TFIIAαβ/γ is also sufficient for bulk transcription during development, possibly via TFIID complex. TFIIAαβ/γ can be cleaved by Taspase 1 into TFIIAα/β/γ that can assemble with TFIID and activate transcription of a subset of genes, such as cell cycle-specific genes. Ultimately, TFIIAα/β/γ is a substrate for proteasome-dependent degradation, possibly through the N-end rule pathway.
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comprehensive analysis of the function of cleaved and uncleaved TFIIA will require genome-wide targeting analyses in wild-type and mutant cells in which endogenous TFIIA is replaced by an uncleavable or pre-cleaved form. The unexpected finding that TFIIA and MLL are substrates of the same protease, Taspase1, raises the intriguing possibility that cleavage of TFIIA and MLL (and other proteins) is coregulated during development. The fact that the substrates for Taspase1 identified so far (TFIIA, MLL and MLL2) are transcription regulators suggests that Taspase1 mediated cleavage may be directly linked to the transcription process. Although the precise regulation and function of TFIIA cleavage remains elusive, it is clear that cleavage is not necessary to obtain transcriptionally competent TFIIA. The biology of the transcription factor TFIIA continues to unveil unexpected layers of complexity decades after its identification. We are looking forward to the next surprises that may lead us to the fully uncovered nature of this elusive transcription factor. References [1] R.G. Roeder, W.J. Rutter, Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms, Nature 224 (1969) 234–237. [2] P. Chambon, F. Gissinger, C. Kedinger, J.L. Mandel, M. Meilhac, P. Nuret, Structural and functional properties of three mammalian nuclear DNA-dependent RNA polymerases, Acta Endocrinol., Suppl. (Copenh) 168 (1972) 222–246. [3] R.G. Roeder, L.B. Schwartz, V.E. Sklar, Function, structure, and regulation of eukaryotic nuclear RNA polymerases, Symp. Soc. Develop. Biol. 34 (1976) 29–52. [4] C.S. Parker, R.G. Roeder, Selective and accurate transcription of the Xenopus laevis 5S RNA genes in isolated chromatin by purified RNA polymerase III, Proc. Natl. Acad. Sci. U. S. A. 74 (1977) 44–48. [5] T. Matsui, J. Segall, P.A. Weil, R.G. Roeder, Multiple factors required for accurate initiation of transcription by purified RNA polymerase II, J. Biol. Chem. 255 (1980) 11992–11996. [6] S.Y. Ng, C.S. Parker, R.G. Roeder, Transcription of cloned Xenopus 5S RNA genes by X. laevis RNA polymerase III in reconstituted systems, Proc. Natl. Acad. Sci. U. S. A. 76 (1979) 136–140. [7] P.A. Weil, J. Segall, B. Harris, S.Y. Ng, R.G. Roeder, Faithful transcription of eukaryotic genes by RNA polymerase III in systems reconstituted with purified DNA templates, J. Biol. Chem. 254 (1979) 6163–6173. [8] M. Samuels, A. Fire, P.A. Sharp, Separation and characterization of factors mediating accurate transcription by RNA polymerase II, J. Biol. Chem. 257 (1982) 14419–14427. [9] D. Reinberg, R.G. Roeder, Factors involved in specific transcription by mammalian RNA polymerase II. Purification and functional analysis of initiation factors IIB and IIE, J. Biol. Chem. 262 (1987) 3310–3321. [10] L. Zawel, D. Reinberg, Advances in RNA polymerase II transcription, Curr. Opin. Cell Biol. 4 (1992) 488–495. [11] G. Orphanides, T. Lagrange, D. Reinberg, The general transcription factors of RNA polymerase II, Genes Dev. 10 (1996) 2657–2683. [12] D. Reinberg, M. Horikoshi, R.G. Roeder, Factors involved in specific transcription in mammalian RNA polymerase II. Functional analysis of initiation factors IIA and IID and identification of a new factor operating at sequences downstream of the initiation site, J. Biol. Chem. 262 (1987) 3322–3330. [13] J.A. Ranish, W.S. Lane, S. Hahn, Isolation of two genes that encode subunits of the yeast transcription factor IIA, Science 255 (1992) 1127–1129. [14] D. Reinberg, R.G. Roeder, Factors involved in specific transcription by mammalian RNA polymerase II. Transcription factor IIS stimulates elongation of RNA chains, J. Biol. Chem. 262 (1987) 3331–3337.
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Review
A facelift for the general transcription factor TFIIA Torill Høiby a,1,2 , Huiqing Zhou a,2 , Dimitra J. Mitsiou b , Hendrik G. Stunnenberg a,⁎ a
NCMLS, Department of Molecular Biology, 191, Radboud University of Nijmegen, PO Box 91001, 6500 HB Nijmegen, The Netherlands Molecular Endocrinology Program, Institute of Biological Research and Biotechnology, The National Hellenic Research Foundation, 48Vas. Constantinou Av, 11635 Athens, Greece
b
Received 7 February 2007; received in revised form 20 April 2007; accepted 24 April 2007 Available online 5 May 2007
Abstract TFIIA was classified as a general transcription factor when it was first identified. Since then it has been debated to what extent it can actually be regarded as “general”. The most notable feature of TFIIA is the proteolytical cleavage of the TFIIAαβ into a TFIIAα and TFIIAβ moiety which has long remained a mystery. Recent studies have showed that TFIIA is cleaved by Taspase1 which was initially identified as the protease for the proto-oncogene MLL. Cleavage of TFIIA does not appear to serve as a step required for its activation as the uncleaved TFIIA in the Taspase1 knock-outs adequately support bulk transcription. Instead, cleavage of TFIIA seems to affect its turn-over and may be a part of an intricate degradation mechanism that allows fine-tuning of cellular levels of TFIIA. Cleavage might also be responsible for switching transcription program as the uncleaved and cleaved TFIIA might have distinct promoter specificity during development and differentiation. This review will focus on functional characteristics of TFIIA and discuss novel insights in the role of this elusive transcription factor. © 2007 Elsevier B.V. All rights reserved. Keywords: TFIIA; Transcription; Taspase1; Cleavage
1. Introduction One of the groundbreaking discoveries in eukaryotic transcription was the identification of nuclear RNA polymerase (Pol) I, II and III that transcribe large ribosomal genes, protein coding and some small nuclear RNA genes, and most small structural RNA genes, respectively [1–3]. The complexity and variability of the general transcription machinery in Eukarya was further extended through the discovery of specific accessory factors [4–7]. The inability of RNA polymerases to initiate transcription by themselves provided the basis for characterising the general transcription factors (GTFs) that reconstitute accurate transcription initiation; for RNA Pol II, they include TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH [8– 11]. Subsequent research has unveiled a multitude of additional (co-)activators, (co-)repressors and multi-protein complexes ⁎ Corresponding author. Tel.: +31 24 3610524; fax: +31 24 3610520. E-mail address: [email protected] (H.G. Stunnenberg). 1 Present address: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. 2 These authors contribute equally to this work. 0167-4781/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbaexp.2007.04.008
that mediate communication between DNA-bound transcription factors and the general transcription machinery. In addition the general transcription machinery itself varies considerably. The role of the general transcription factor TFIIA has been particularly elusive. In initial studies the TFIIA-containing fraction was necessary to reconstitute basal transcription in vitro [12]. Consequently, TFIIA was classified as a general transcription factor, which was later debated because of contradicting results as to its role in transcription. Recent data suggest that promoters vary widely in their requirement for TFIIA for transcriptional activation, and it appears that TFIIA may not be generally involved in transcription but may possess promoter-specificity during development and differentiation. This review will discuss TFIIA from a transcriptional point of view with an emphasis on its proteolytical cleavage by Taspase1, its regulation and consequences thereof. 2. The role of TFIIA in general transcription Functional and biochemical studies have concluded differently as to the role TFIIA in transcription, and TFIIA has been described as essential [13,14], stimulatory [8] or dispensable
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[15,16]. These inconsistencies are generally believed to originate from the impurities in the factors/fractions used in the respective in vitro transcription studies. TFIIA has been shown to stimulate transcription by stabilizing TBP binding to the TATA box [17] and by regulating TBP or TFIID dimerization to accelerate DNA binding. However, it does not appear to stimulate TBP-mediated transcription from a core promoter when using highly purified factors [18–21]. In complementation assays using partially purified factors, TFIIA has a stimulatory effect, presumably by reversing the inhibitory effects of negative co-factors like NC1, Dr1/NC2, Dr2/Topo1, HMG1 and DSP1, as well as by counteracting the effects of BTAF1 and TAF1 [18,22–29]. TFIIA is crucial for basal and activated transcription from TATA-less promoters in vitro, suggesting that it has a core promoter-specific role beyond stabilizing TBP binding to DNA [30]. Furthermore, TFIIA functions as a co-activator for several activators (AP-1, Gal4AH, Zta, VP16, CTF, NTF, Sp1) [18,19,31–33] and enhances the effect of co-activators like PC4 and HMG2 [20,34]. Additionally, some studies have implied TFIIA in RNA Pol III transcription, for example on the 5S and U6 RNA promoters [35,36], whereas this has been contradicted by other results [37–39]. Various approaches have been employed to study the function of TFIIA in vivo e.g. by disrupting the TBP–TFIIA–DNA interaction. Stargell and Struhl employed a yeast TBP mutant impaired in its interaction with TFIIA and demonstrated a specific impairment in the response to acidic activators, whereas bulk RNA Pol II transcription was unaffected [40]. Selective transcriptional effects and a partial inhibition of cell-cycle progression [41] have been observed by Ozer et al. upon diminishing the interactions between TFIIA and TBP. Subsequent studies have shown that a ten times depletion of TFIIA leads to a moderate decrease in RNA Pol II transcription from both TATA-containing and TATA-less promoters [38] and a wide variety of genes is affected minimally (2–3 fold) when TFIIA is reduced to less than 1% of the wild-type level [37]. These mild effects are in contrast to the depletion of general transcription factors like TBP, TFIIB, TFIIH subunits and RNA Pol II subunits which leads to a total elimination of RNA Pol II transcription in yeast [37]. However, TFIIA depleted cells do arrest specifically at G2/M arguing that TFIIA has an important role in controlling genes related to cell cycle progression. The moderate effects on transcription upon TFIIA depletion could be explained by Mot1 functionally replacing TFIIA in preinitiation complexes, as shown in yeast studies by Geisberg and Struhl where Mot1 co-occupies promoters with TBP, TFIIB and Pol II after stress [42]. This hypothesis is supported by the observation that Mot1 can assist in recruiting TBP to promoters during gene activation, much in the same way TFIIA is thought to do [43,44]. One unifying explanation would be that TFIIA acts more like a co-activator than as a general factor. In support of this hypothesis, TFIIA has been reported to interact, either physically or genetically, with a number of factors (summarised in Table 1), including general transcription factors like TFIID or SAGA components as well as repressors. These observations support a model in which TFIIA functions by communicating
between activators and the general transcription machinery, modulating the activities of the TFIID and SAGA components, and counterbalancing the effect of repressors. Based on its coactivating characteristics and association with TBP, TFIIA has also been proposed to be a TBP-associated factor (TAF) that dissociates from the TFIID complex more readily than the other TAFs [47]. This model is in agreement with the identification of the TBP–TFIIA containing Complex (TAC) consisting of TBP and TFIIA but no classical TAFs. To classify TFIIA as a TAF may, however, also be inappropriate; recent in vivo studies in yeast have shown that the TBP/TAF ratio varies significantly amongst different promoters in contrast to the TBP/TFIIA ratio [63]. This suggests that some TFIIA-dependent genes are TAFindependent, whereas others are TAF-dependent. 3. The architecture of the TFIIA and its paralogue ALF Budding yeast (S. cerevisiae) TFIIA was originally purified as a complex consisting of two polypeptides with molecular masses of 32 and 13.5 kDa [64] encoded by TOA1 and TOA2, that are both essential in yeast [13]. In contrast, TFIIA was found to be composed of three polypeptides, α, β and γ, in Homo sapiens and Drosophila melanogaster [18,51,65]. Cloning of TFIIA revealed that the two larger subunits, α and β, are encoded by a single gene and post-translationally processed. TFIIAαβ and TFIIAγ in higher eukaryotes are the respective homologues of the yeast subunits TOA1 and TOA2 [18,51,65] (Fig. 1). The crystal structure of yeast TFIIA/TBP/DNA complex revealed that the two yeast TFIIA subunits are intimately associated in two domains: a six-stranded β-sandwich domain that is composed of two β-sheets and a left-handed four-helix bundle Table 1 TFIIA-interacting proteins Factor
Function
Reference
AP-1 Zta VP16 CTF NTF SP1 GAL4 PC4 HMG2 scTAF11 dmTAF4 TBP TRF2 CREM GCN5 SWI2 NHP6 TAF1 BTAF1 NC2 HMGB1 RBP SPT3 SPT8
Activator of transcription Activator of transcription Activator of transcription Activator of transcription Activator of transcription Activator of transcription Activator of transcription Co-activator of transcription Co-activator of transcription TBP-associated factor TBP-associated factor TATA-binding protein TBP-related factor 2 Activator of transcription in germ cells Histone acetylase, component of SAGA Chromatin remodeling Architectural gene modulation TBP-associated factor Repressor of transcription Repressor of transcription Repressor of transcription Repressor of transcription Component of SAGA Component of SAGA
[45] [19,45,46] [45–47] [45] [31] [31] [45,48] [49] [34] [50] [51] [50–53] [54] [55] [56] [56] [56] [25,27,29] [44] [57,58] [59] [60] [61] [62]
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Fig. 1. Structural comparison of S. cerevisiae TFIIA (TOA1 and TOA2), human TFIIA (hTFIIAαβ and hTFIIAγ) and human ALF. The four-helix bundle (FHB) domain and the β-barrel domain identified in the crystal studies as well as the spacer domain, the acidic domain and the Cleavage Recognition Site (CRS) are indicated.
domain. The β-sandwich domain interacts with the N-terminal stirrup region of TBP and with the backbone of the TATA box whereas the four-helix bundle projects away from the TFIIA/ TBP/DNA complex and is available for additional interactions with transcription factors [66,67]. Interaction of TFIIA with TBP and DNA places TFIIA immediately upstream of the TATA box on the opposite side of DNA from TFIIB [66–68], indicating the role of TFIIA in the preinitiation complex. Comparison of the crystal structure between the human and yeast TFIIA/TBP/DNA complex revealed conserved architecture [69]. The high sequence and structural conservation of TFIIA from yeast to human underlines the significance of TFIIA in fundamental aspects of eukaryotic transcription. The highly conserved N- and C-terminal domains of TOA1 are essential but a significant portion of the non-conserved middle region can be removed without loss of viability in yeast. In contrast, introducing the human acidic region or the very C-terminal region of TFIIAαβ into TOA1 has severe effects on yeast growth [38]. Thus, despite the overall conservation, some protein properties are not conserved across species [70], although it is not clear what the functions of these domains are. The general transcription factors were long believed to be unique and essential for transcription of all RNA Pol II promoters. This view was challenged by the discovery of cell- and tissuespecific paralogues in higher eukaryotes of two of the general transcription factors. Hitherto, paralogues have only been identified for TBP and TFIIA, whereas RNA Pol II, TFIIB, TFIIE, TFIIF and TFIIH are all present as a single gene in the D. melanogaster, Caenorhabditis elegans and mammalian genomes. TBP is in fact supplemented with at least three paralogues in metozoans; the insect-specific TRF1 [71–73], the TLF/TRF2 which is found in all metozoan genomes examined thus far [74– 78] and the vertebrate TBP2 [79,80]. TFIIA turned out to have
one paralogue, the TFIIA-Like Factor (ALF) [81–84], which is also subject to proteolytic cleavage [85,86]. Expression patterns of TFIIA, ALF, TBP paralogues and TAF variants revealed that transcription during gametogenesis and early embryogenesis could be regulated by diverse developmental and cell typespecific transcription factor complexes. For example in both Xenopus and mice, ALF and TBP2 are specifically coexpressed in oocytes, and their expression levels are reduced during fertilization; in contrast, their somatic counterparts TFIIAαβ and TBP transcripts are present in somatic cells as well as reproductive tissues [87,88]. In Xenopus and mammalian cells, only one TFIIAγ subunit has been identified so far, indicating that TFIIAγ interacts with both TFIIAαβ and ALF to form a heterodimeric complex that stabilizes binding of TBP to promoter DNA. Interestingly, rice has shown to have two TFIIAγ-like genes, TFIIAγ1 and Xa5 (TFIIAγ5). Xa5/xa5, a V39E substitution variant of TFIIAγ1, was functionally confirmed to confer resistance to rice bacterial blight, suggesting that duplication of the TFIIAγ gene gives rise to a new function for disease resistance during evolution [89]. An archeal homologue of TFIIA is missing [90], which may mean that TFIIA has evolved in organisms that require a more elaborate regulation of transcriptional activation. 4. Cleavage of TFIIA by Taspase1 In initial studies, the uncleaved TFIIAαβ was not detected in cell extracts, which led to the assumption that cleavage of TFIIA occurs directly after or during translation, and the cleaved TFIIA was seen as the functional form [19,65]. Years later this point of view had to be reconsidered because studies in P19 embryonal carcinoma (EC) cells revealed considerable levels of the uncleaved form of TFIIAαβ which was shown to be transcriptionally active. In P19 EC and other embryonal cells,
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the uncleaved form of TFIIA interacts stably with TBP in a TAFfree complex termed TAC [91]. TAC formation is stimulated by the co-activator p300 in EC cells, and over-expression of p300 appears to facilitate formation of TAC also in other cells [92]. These observations provided the first hint that cleavage of TFIIAαβ is a regulated event that may be linked to the differentiation state of cells, and motivated renewed efforts to identify the TFIIA cleavage site and the protease(s) involved. The mapping and characterisation of the human TFIIA cleavage site led to the delineation of the cleavage recognition sequence (CRS), a string of four residues (272–275) that are essential for TFIIA cleavage [85]. The importance of the CRS was underscored by its strict conservation amongst higher eukaryotes (Fig. 2). The identification of the protease responsible for TFIIA cleavage was greatly helped by the observation that the CRS of TFIIA is identical to the protease cleavage site of the protooncogene Mixed-Lineage Leukemia (MLL) [93], and consistent with that, MLL and TFIIA were shown to be cleaved by the same protease, Taspase1 [94,95]. Taspase1 cleaves human TFIIA at D274/G275 within the highly conserved CRS [95]. In line with this observation, studies on the TFIIA-like factor (ALF) indicate that the cleavage site of ALF is at D341/G342, corresponding to D274/G275 in human TFIIA [86]. From an evolutionary point of view, the cleavage process appears to have evolved subsequent to the divergence of S. cerevisiae where TFIIA does not have a CRS and consistently, a Taspase1 like L-asparaginase is absent. In contrast, the TFIIA of fission yeast (Schizosaccharomyces pombe), A. thaliana and C. elegans all contain a CRS (Fig. 2) and their genomes encode a Taspase1-like factor (Hoiby and Stunnenberg, unpublished data). It is therefore conceivable that TFIIA undergoes cleavage in these organisms, suggesting that cleavage plays a role in TFIIA regulation and function in higher organisms beyond S. cerevisiae.
Fig. 2. Alignment of the CRS and the cleavage site of TFIIA and MLL from different organisms, H. sapiens (h), Mus musculus (m), X. laevis (x), D. melanogaster (d), C. elegans (e), Arabidopsis thaliana (a), S. pombe (sp) and Takifugu rubripes (r). The conserved CRS is boxed. Cleavage of TFIIA and MLL by Taspase1 is at D/G, indicated with an arrow. D278 marked with ⋄ is the identified Nterminal end of the β subunit of TFIIA purified from mammalian cells.
5. Regulation of cleavage In contrast to earlier reports that the uncleaved TFIIA was not detectable in crude cell extracts, it has been detected in all cell lines investigated so far when cell extracts are fractionated through a Ni-NTA column. The abundance of the uncleaved TFIIA appears to vary in different cell lines, with P19 EC cells hitherto showing the highest ratio of uncleaved to cleaved TFIIA. Whether regulation of TFIIA cleavage occurs by regulation of the Taspase1 activity or by post-translational modification of TFIIA that interferes with cleavage remains to be investigated. One such modification may well be phosphorylation, since mimicking phosphorylation by the mutation T276D adjacent to the CRS renders TFIIA uncleavable, whereas mutant T276A behaves like wild-type TFIIA ([85] and Høiby, T. and Stunnenberg, H.G., unpublished data). Furthermore, putative phosphorylation sites (T276, T279, S280, S281) close to the CRS seem to affect TFIIA stability [85], and their potential kinase casein kinase II (CKII) has been implicated in promoter selection and in the regulation of a number of transcription factors [96–98]. In addition to phosphorylation, acetylation is another modification that might affect cleavage of TFIIA because the stimulatory role of p300 in TAC formation is dependent on its HAT activity, and consistently, the uncleaved form of TFIIAαβ is preferentially acetylated [92]. The exact role of p300 in regulation of TFIIA cleavage can at present only be speculated upon, but it may affect the efficacy of cleavage, either directly or by modulating the Taspase1 activity. 6. The function of TFIIA cleavage Until the recent efforts to investigate the cleavage site of TFIIA and its function, the general view was that cleavage renders TFIIA transcriptionally active. Our studies have shown that inhibition of cleavage through a single mutation in the CRS such as G275A significantly prolonged the half-life of TFIIA [85]. Cleaved TFIIAα and -β but not uncleaved TFIIAαβ are substrates for proteasomal degradation, indicating that the level of TFIIA is regulated by cleavage. These observations lead to a new concept that the function of cleavage may be to initiate a TFIIA degradation pathway which could be directly or indirectly linked to transcription. Several reports conclude that cellular TFIIA levels fluctuate; for example, TFIIA expression declines dramatically upon HSV virus infection, which suggests that regulation of TFIIA levels is part of a cellular program enabling the transition from early to late viral gene transcription during infection, and implies a requirement for TFIIA in transcription of early but not late genes [99]. Furthermore, inactivation of TFIIA during terminal differentiation of avian erythroid cells correlates to a general repression of gene activity in these cells [100], and TFIIAγ expression is up-regulated during Ras-mediated photoreceptor induction in D. melanogaster [101]. Collectively, these results suggest that regulation of cellular TFIIA levels contributes to the regulation of gene expression during processes such as cell differentiation and transformation. Regulating TFIIA stability and TFIIA cleavage seems to be one way to achieve this.
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Initially, the N-terminus of the human TFIIAβ subunit was identified as D278 [85] by sequencing the β subunit purified from FM3A cells stably expressing human TFIIAαβ. However, N-terminal sequencing of in vitro Taspase1-cleaved TFIIA revealed that its cleavage site was between D274/G275 which is identical to the cleavage site determined for MLL [95] and 3 amino acids upstream of the previously identified N-terminus (Fig. 2). The apparent inconsistency may be the result of a secondary cleavage in vivo by either an endo- or an exopeptidase activity. Such a secondary cleavage would generate a potential N-terminal degron in TFIIA, D278, and TFIIA cleavage could thus be a step of the N-end rule destruction pathway to regulate the level and transcriptional activity of TFIIA. Interestingly, studies in embryonal P19 cells unexpectedly showed that the uncleaved TFIIA interacts with TBP and participates in a transcriptionally competent complex, TAC [91]. This study raised the question whether the uncleaved and cleaved TFIIA have distinct target genes and whether cleavage may be critical for changing specific transcription programs and hence play a role in differentiation and development. The uncleaved TFIIA and TAC were hypothesized to be components of the transcription machinery specific for embryonic development, whereas cleaved TFIIA could be involved in TFIID-mediated transcription for general promoters (Fig. 3). Recently, this new model has been modified once again based on emerging data. The protease for TFIIA cleavage, Taspase1, has been knocked-out in the mouse model, and Taspase1−/− MEF cells in which only uncleaved TFIIA was detected could be established [95]. Taspase1 knock-out mice survived till birth and showed minor overall defects [102], indicating that the uncleaved form of TFIIA is functional. In Xenopus, an uncleavable TFIIA mutant (G269A, corresponding to G275A in human) was able to rescue TFIIA knock-down embryos in both development and gene expression [95], which is in full agreement with a model in which the uncleaved form of TFIIA is transcriptionally active in early embryogenesis and sufficient
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for bulk transcription. Whether the functional uncleaved TFIIA is in the TAC complex or plays its transcriptional role via the TFIID complex is yet to be determined. It is possible that in early developmental stages, uncleaved TFIIA is sufficient for transcription, and at later stages cleavage of TFIIA is important for expression of a subset of genes. Recent data from Taspase1−/− MEFs showed that these cells in which TFIIA remains uncleaved exhibit cell cycle defects, indicating that uncleaved substrate(s) of Taspase1 is (are) responsible for these defects. TFIIA, one of the substrates identified thus far, was previously shown to be important for cell cycle progression [41]; therefore, it will be interesting to test whether the cleaved TFIIA is involved in cell cycle control (Fig. 3). 7. Perspectives Over the past 20 years, TFIIA has transformed from a rather inconspicuous protein that plays a role in transcription in a vaguely described manner to a transcription factor that appears to be tightly regulated with a particular role in differentiation and development. The presence of the CRS and the corresponding Taspase1-like protease recognizing the CRS indicates that cleavage of TFIIA has evolved subsequent to the divergence of S. cerevisiae, allowing a more delicate transcriptional control in higher organisms. The observation that the uncleaved TFIIA is sufficient for bulk transcription in early embryogenesis raises questions as to the particular function of cleavage and of the cleaved form itself which represents the vast majority of TFIIA in most differentiated cells. The cleaved form may play a specific transcriptional role regulating a subset of genes like cell cyclerelated genes at later developmental stages and/or it may be involved in bulk transcription and partially overlap with the function of the uncleaved TFIIA (Fig. 3). The cleaved TFIIA may also be a transient by-product of a transcriptionally linked cleavage process that is about to be degraded (Fig. 3). A
Fig. 3. Model for function of TFIIA. Uncleaved TFIIAαβ/γ can assemble with TBP into TAC and this is facilitated, directly or indirectly, by p300. TAC is responsible for the transcriptional activation of hitherto unknown embryo-specific promoters. Uncleaved TFIIAαβ/γ is also sufficient for bulk transcription during development, possibly via TFIID complex. TFIIAαβ/γ can be cleaved by Taspase 1 into TFIIAα/β/γ that can assemble with TFIID and activate transcription of a subset of genes, such as cell cycle-specific genes. Ultimately, TFIIAα/β/γ is a substrate for proteasome-dependent degradation, possibly through the N-end rule pathway.
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