TFIIH is a multiprotein complex that is involved in various cellular processes, including nucleotide excision repair (NER) and transcription, revealing the tight molecular connections between transcription and DNA repair.
During NER, TFIIH promotes the opening of DNA around a lesion, which requires the helicase activity of its XPD subunit and the ATPase activity of its XPB subunit.
During transcription of protein coding genes, the ATP-dependent helicase activity of XPB is required for promoter opening, and the cyclin-dependent kinase 7 (CDK7) kinase subunit of TFIIH promotes the phosphorylation of RNA polymerase II to initiate transcription. Additionally, CDK7 is involved in transactivation by phosphorylating transcription factors such as nuclear receptors.
Mutations in three subunits of TFIIH (XPB, XPD and p8) give rise to the autosomal recessive disorders xeroderma pigmentosum (which is sometimes associated with Cockayne syndrome) and trichothiodystrophy (TTD).
Disorders related to TFIIH mutations were initially defined as DNA repair syndromes. However, recent advances reveal the tight connection between transcription and DNA repair, which suggests that the clinical complexity of these syndromes results from defects in both processes.
The transcription initiation factor TFIIH is a remarkable protein complex that has a fundamental role in the transcription of protein-coding genes as well as during the DNA nucleotide excision repair pathway. The detailed understanding of how TFIIH functions to coordinate these two processes is also providing an explanation for the phenotypes observed in patients who bear mutations in some of the TFIIH subunits. In this way, studies of TFIIH have revealed tight molecular connections between transcription and DNA repair and have helped to define the concept of 'transcription diseases'.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Bohr, V. A., Smith, C. A., Okumoto, D. S. & Hanawalt, P. C. DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell 40, 359–369 (1985).
Mellon, I., Spivak, G. & Hanawalt, P. C. Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Cell 51, 241–249 (1987).
Schaeffer, L. et al. DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science 260, 58–63 (1993). Demonstrated that the helicase XPB, which is involved in NER, is closely associated with the TFIIH transcription complex, suggesting that DNA repair and transcription are functionally related.
Feaver, W. J. et al. Dual roles of a multiprotein complex from S. cerevisiae in transcription and DNA repair. Cell 75, 1379–1387 (1993).
Schmitz, K. M. et al. TAF12 recruits Gadd45a and the nucleotide excision repair complex to the promoter of rRNA genes leading to active DNA demethylation. Mol. Cell 33, 344–353 (2009). Revealed that the DNA repair machinery is recruited to the promoter of active genes, keeping these promoters in a hypomethylated state.
Le May, N. et al. NER factors are recruited to active promoters and facilitate chromatin modification for transcription in the absence of exogenous genotoxic attack. Mol. Cell 38, 54–66 (2010). Showed the sequential recruitment of the NER factors XPC, XPA, RPA, XPG and XPF–ERCC1 to the promoters of inducible genes in the absence of exogenous genotoxic attack. These NER factors (except cockayne syndrome B protein (CSB; also known as ERCC6)) are required to allow histone modifications and active DNA demethylation that are necessary for efficient transcription.
Conaway, R. C. & Conaway, J. W. An RNA polymerase II transcription factor has an associated DNA-dependent ATPase (dATPase) activity strongly stimulated by TATA region of promoters. Proc. Natl Acad. Sci. USA 86, 7356–7360 (1989). Reported the purification of a transcription factor from rat liver that was designated transcription factor-δ, which has an associated DNA-dependent ATPase activity.
Gerard, M. et al. Purification and interaction properties of the human RNA polymerase B(II) general transcription factor BTF2. J. Biol. Chem. 266, 20940–20945 (1991). Described the purification of the human cell transcription factor BTF2, which is required for the transcription of class II genes.
Feaver, W. J., Gileadi, O. & Kornberg, R. Purification and characterization of yeast RNA polymerase II transcription factor b. J. Biol. Chem. 266, 19000–19005 (1991). Reported the purification of a transcription factor from yeast that was designated Tfb, which is required for Pol II transcription.
Flores, O., Lu, H. & Reinberg, D. Factors involved in specific transcription by mammalian RNA polymerase II. Identification and characterization of factor IIH. J. Biol. Chem. 267, 2786–2793 (1992).
Schaeffer, L. et al. The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. EMBO J. 13, 2388–2392 (1994).
Weber, C. A., Salazar, E. P., Stewart, S. A. & Thompson, L. H. ERCC2: cDNA cloning and molecular characterization of human nucleotide excision repair gene with high homology to yeast RAD3. EMBO J. 9, 1437–1447 (1990).
Weeda, G., Ma, L., van der Ham, R., van der Eb, A. J. & Hoeijmakers, J. H. J. Structure and expression of the human XPBC/ERCC-3 gene involved in DNA repair disorders xeroderma pigmentosum and Cockayne's syndrome. Nucleic Acids Res. 19, 6301–6308 (1991).
Feaver, W. J., Gileadi, O., Li, Y. & Kornberg, R. D. CTD kinase associated with yeast RNA polymerase II initiation factor b. Cell 67, 1223–1230 (1991).
Roy, R. et al. The MO15 cell cycle kinase is associated with the TFIIH transcription-DNA repair factor. Cell 79, 1093–1101 (1994). Revealed that MO15 (also known as CDK7) kinase is present in the TFIIH transcription complex.
Fisher, R. P. & Morgan, D. O. A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell 78, 713–724 (1994).
Mäkelä, T. P. et al. A cyclin associated with the CDK-associated kinase MO15. Nature 371, 254–257 (1994).
Adamczewski, J. P. et al. MAT1, cdk7 and cyclin H form a kinase complex which is UV light-sensitive upon association with TFIIH. EMBO J. 15, 1877–1884 (1996).
Rossignol, M., Kolb-Cheynel, I. & Egly, J. M. Substrate specificity of the cdk-activating kinase (CAK) is altered upon association with TFIIH. EMBO J. 16, 1628–1637 (1997).
Larochelle, S., Pandur, J., Fisher, R. P., Salz, H. K. & Suter, B. Cdk7 is essential for mitosis and for in vivo Cdk-activating kinase activity. Genes Dev. 12, 370–381 (1998).
Fesquet, D., Morin, N., Doree, M. & Devault, A. Is Cdk7/cyclin H/MAT1 the genuine cdk activating kinase in cycling Xenopus egg extracts? Oncogene 15, 1303–1307 (1997).
Wu, L. et al. RNA antisense abrogation of MAT1 induces G1 phase arrest and triggers apoptosis in aortic smooth muscle cells. J. Biol. Chem. 274, 5564–5572 (1999).
Aprelikova, O., Xiong, Y. & Liu, E. T. Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase. J. Biol. Chem. 270, 18195–18197 (1995).
Fesquet, D. et al. The MO15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin dependent kinases (CDKs) through phosphorylation of Thr161 and its homologues. EMBO J. 12, 3111–3121 (1993).
Matsuoka, M., Kato, J. Y., Fisher, R. P., Morgan, D. O. & Sherr, C. J. Activation of cyclin-dependent kinase 4 (cdk4) by mouse MO15-associated kinase. Mol. Cell. Biol. 14, 7265–7275 (1994).
Poon, R. Y. C., Yamashita, K., Adamczewski, J. P., Hunt, T. & Shuttleworth, J. The cdc2-related protein p40MO15 is the catalytic subunit of a protein kinase that can activate p33cdk2 and p34cdc2. EMBO J. 12, 3123–3132 (1993).
Solomon, M. J., Harper, W. J. & Shuttleworth, J. CAK, the p34cdc2 activating kinase contains a protein kinase identical to or closely related to p40MO15. EMBO J. 12, 3133–3142 (1993).
Fisher, R. P. Secrets of a double agent: CDK7 in cell-cycle control and transcription. J. Cell Sci. 118, 5171–5180 (2005).
Ito, S. et al. MMXD, a TFIIH-independent XPD–MMS19 protein complex involved in chromosome segregation. Mol. Cell 39, 632–640 (2010).
Sancar, A. Mechanisms of DNA excision repair. Science 266, 1954–1956 (1994).
Aboussekhra, A. et al. Mammalian DNA nucleotide excision repair reconstituted with purified protein components. Cell 80, 859–868 (1995).
Volker, M. et al. Sequential assembly of the nucleotide excision repair factors in vivo. Mol. Cell 8, 213–224 (2001).
Hanawalt, P. C. & Spivak, G. Transcription-coupled DNA repair: two decades of progress and surprises. Nature Rev. Mol. Cell Biol. 9, 958–970 (2008).
Clement, F. C. et al. Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein. Mutat. Res. 685, 21–28 (2010).
Bunick, C. G., Miller, M. R., Fuller, B. E., Fanning, E. & Chazin, W. J. Biochemical and structural domain analysis of xeroderma pigmentosum complementation group C protein. Biochemistry 45, 14965–14979 (2006).
Min., J. H. & Pavletich, N. P. Recognition of DNA damage by the Rad4 nucleotide excision repair protein. Nature 449, 570–575 (2007).
Sugasawa, K. et al. A multistep damage recognition mechanism for global genomic nucleotide excision repair. Genes Dev. 15, 507–521 (2001).
Mocquet, V. et al. The human DNA repair factor XPC–HR23B distinguishes stereoisomeric benzo[a]pyrenyl-DNA lesions. EMBO J. 26, 2923–2932 (2007).
Keeney, S., Chang, G. J. & Linn, S. Characterization of a human DNA damage binding protein implicated in xeroderma pigmentosum E. J. Biol. Chem. 268, 21293–21300 (1993).
Takao, M. et al. A 127 kDa component of a UV-damaged DNA-binding complex which is defective in some xeroderma pigmentosum group E patients is homologous to a slime mold protein. Nucleic Acids Res. 21, 4111–4118 (1993).
Fitch, M. E. et al. The DDB2 nucleotide excision repair gene product p48 enhances global genomic repair in p53 deficient human fibroblasts. DNA Repair (Amst.) 2, 819–826 (2003).
Wang, Q. E., Zhu, Q., Wani, G., Chen, J. & Wani, A. A. UV radiation-induced XPC translocation within chromatin is mediated by damaged-DNA binding protein, DDB2. Carcinogenesis 25, 1033–1043 (2004).
Fei, J. et al. Regulation of nucleotide excision repair by UV-DDB: prioritization of damage recognition to internucleosomal DNA. PLoS Biol. 9, e1001183 (2011).
Gillette, T. G. et al. Distinct functions of the ubiquitin–proteasome pathway influence nucleotide excision repair. EMBO J. 25, 2529–2538 (2006).
Araki, M. et al. Centrosome protein centrin 2/caltractin 1 is part of the xeroderma pigmentosum group C complex that initiates global genome nucleotide excision repair. J. Biol. Chem. 276, 18665–18672 (2001).
Xie, Z., Liu, S., Zhang, Y. & Wang, Z. Roles of Rad23 protein in yeast nucleotide excision repair. Nucleic Acids Res. 32, 5981–5990 (2004).
Tapias, A. et al. Ordered conformational changes in damaged DNA induced by nucleotide excision repair factors. J. Biol. Chem. 279, 19074–19083 (2004).
Bernardes de Jesus, B. M., Bjoras, M., Coin, F. & Egly, J. M. Dissection of the molecular defects caused by pathogenic mutations in the DNA repair factor XPC. Mol. Cell. Biol. 28, 7225–7235 (2008).
Bootsma, D. & Hoeijmakers, J. H. J. DNA repair. Engagement with transcription. Nature 363, 114–115 (1993).
Wood, R. D. DNA damage recognition during nucleotide excision repair in mammalian cells. Biochimie 81, 39–44 (1999).
Coin, F. et al. Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH. Nature Genet. 20, 184–188 (1998). Demonstrated that mutations in the XPD C-terminal domain that are found in most patients with xeroderma pigmentosum and TTD prevent the interaction with p44, thus explaining the observed decrease in XPD helicase activity and the NER defect.
Dubaele, S. et al. Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients. Mol. Cell 11, 1635–1646 (2003).
Tirode, F., Busso, D., Coin, F. & Egly, J. M. Reconstitution of the transcription factor TFIIH: assignment of functions for the three enzymatic subunits, XPB, XPD, and cdk7. Mol. Cell 3, 87–95 (1999).
Oksenych, V., de Jesus, B. B., Zhovmer, A., Egly, J. M. & Coin, F. Molecular insights into the recruitment of TFIIH to sites of DNA damage. EMBO J. 28, 2971–2980 (2009).
Fan, L. et al. Conserved XPB core structure and motifs for DNA unwinding: implications for pathway selection of transcription or excision repair. Mol. Cell 22, 27–37 (2006).
Coin, F., Oksenych, V. & Egly, J. M. Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair. Mol. Cell 26, 245–256 (2007). Revealed that the helicase activity of XPB is not used for damaged DNA opening, which is instead driven by the ATPase activity of XPB in combination with the helicase activity of XPD. Furthermore, TFIIH from patients with mutated XPB is unable to induce DNA opening around the lesion owing to impaired XPB–p52 interaction and ATPase stimulation.
Fregoso, M. et al. DNA repair and transcriptional deficiencies caused by mutations in the Drosophila p52 subunit of TFIIH generate developmental defects and chromosome fragility. Mol. Cell. Biol. 27, 3640–3650 (2007).
Fan, L. et al. XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations. Cell 133, 789–800 (2008).
Liu, H. et al. Structure of the DNA repair helicase XPD. Cell 133, 801–812 (2008).
Wolski, S. C. et al. Crystal structure of the FeS cluster-containing nucleotide excision repair helicase XPD. PLoS Biol. 6, e149 (2008).
Mathieu, N., Kaczmarek, N. & Naegeli, H. Strand- and site-specific DNA lesion demarcation by the xeroderma pigmentosum group D helicase. Proc. Natl Acad. Sci. USA 107, 17545–17550 (2010).
Theis, K., Chen, P. J., Skorvaga, M., Van Houten, B. & Kisker, C. Crystal structure of UvrB, a DNA helicase adapted for nucleotide excision repair. EMBO J. 18, 6899–6907 (1999).
Skorvaga, M., Theis, K., Mandavilli, B. S., Kisker, C. & Van Houten, B. The β-hairpin motif of UvrB is essential for DNA binding, damage processing, and UvrC-mediated incisions. J. Biol. Chem. 277, 1553–1559 (2002).
Reardon, J. T. & Sancar, A. Recognition and repair of the cyclobutane thymine dimer, a major cause of skin cancers, by the human excision nuclease. Genes Dev. 17, 2539–2551 (2003).
Stefanini, M., Botta, E., Lanzafame, M. & Orioli, D. Trichothiodystrophy: from basic mechanisms to clinical implications. DNA Repair (Amst.) 9, 2–10 (2010).
Ranish, J. A. et al. Identification of TFB5, a new component of general transcription and DNA repair factor IIH. Nature Genet. 36, 707–713 (2004).
Giglia-Mari, G. et al. A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A. Nature Genet. 36, 714–719 (2004). Demonstrated that p8 is an evolutionarily conserved subunit of TFIIH and identified GTF2H5 as the gene that causes the NER defect in TTD-A.
Coin, F. et al. p8/TTD-A as a repair-specific TFIIH subunit. Mol. Cell 21, 215–226 (2006).
Vermeulen, W. et al. Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder. Nature Genet. 26, 307–313 (2000).
Vitorino, M. et al. Solution structure and self-association properties of the p8 TFIIH subunit responsible for trichothiodystrophy. J. Mol. Biol. 368, 473–480 (2007).
Kainov, D. E., Vitorino, M., Cavarelli, J., Poterszman, A. & Egly, J. M. Structural basis for group A trichothiodystrophy. Nature Struct. Mol. Biol. 15, 980–984 (2008).
Park, C. H. & Sancar, A. Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins. Proc. Natl Acad. Sci. USA 91, 5017–5021 (1994).
Krasikova, Y. S., Rechkunova, N. I., Maltseva, E. A., Petruseva, I. O. & Lavrik, O. I. Localization of xeroderma pigmentosum group A protein and replication protein A on damaged DNA in nucleotide excision repair. Nucleic Acids Res. 38, 8083–8094 (2010).
Ikegami, T. et al. Solution structure of the DNA- and RPA-binding domain of the human repair factor XPA. Nature Struct. Biol. 5, 701–706 (1998).
Saijo, M., Kuraoka, I., Masutani, C., Hanaoka, F. & Tanaka, K. Sequential binding of DNA repair proteins RPA and ERCC1 to XPA in vitro. Nucleic Acids Res. 24, 4719–4724 (1996).
Evans, E., Moggs, J. G., Hwang, J. R., Egly, J. M. & Wood, R. D. Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. EMBO J. 16, 6559–6573 (1997).
Coin, F. et al. Nucleotide excision repair driven by the dissociation of CAK from TFIIH. Mol. Cell 31, 9–20 (2008). Showed the release of CAK from the core TFIIH during the engagement of this complex in DNA repair. Following repair, CAK reappears with the core subunit of TFIIH on chromatin, coincident with the resumption of transcription.
Svejstrup, J. Q. et al. Different forms of TFIIH for transcription and DNA repair: holo-TFIIH and a nucleotide excision repairosome. Cell 80, 21–28 (1995).
Araujo, S. J. et al. Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK. Genes Dev. 14, 349–359 (2000).
Sandrock, B. & Egly, J. M. A yeast four-hybrid system identifies Cdk-activating kinase as a regulator of the XPD helicase, a subunit of transcription factor IIH. J. Biol. Chem. 276, 35328–35333 (2001).
Fan, W. & Luo, J. SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Mol. Cell 39, 247–258 (2010).
Sugasawa, K., Akagi, J., Nishi, R., Iwai, S. & Hanaoka, F. Two-step recognition of DNA damage for mammalian nucleotide excision repair: directional binding of the XPC complex and DNA strand scanning. Mol. Cell 36, 642–653 (2009).
Naegeli, H. & Sugasawa, K. The xeroderma pigmentosum pathway: decision tree analysis of DNA quality. DNA Repair (Amst.) 10, 673–683 (2011).
Kesseler, K. J., Kaufmann, W. K., Reardon, J. T., Elston, T. C. & Sancar, A. A mathematical model for human nucleotide excision repair: damage recognition by random order assembly and kinetic proofreading. J. Theor. Biol. 249, 361–275 (2007).
Mocquet, V. et al. Sequential recruitment of the repair factors during NER: the role of XPG in initiating the resynthesis step. EMBO J. 27, 155–167 (2008).
Staresincic, L. et al. Coordination of dual incision and repair synthesis in human nucleotide excision repair. EMBO J. 28, 1111–1120 (2009).
Moggs, J. G., Yarema, K. J., Essigmann, J. M. & Wood, R. D. Analysis of incision sites produced by human cell extracts and purified proteins during nucleotide excision repair of a 1,3-intrastrand d(GpTpG)-cisplatin adduct. J. Biol. Chem. 271, 7177–7186 (1996).
Gillet, L. C. & Scharer, O. D. Molecular mechanisms of mammalian global genome nucleotide excision repair. Chem. Rev. 106, 253–276 (2006).
Lehmann, A. R. DNA polymerases and repair synthesis in NER in human cells. DNA Repair (Amst.) 10, 730–733 (2011).
Ogi, T. et al. Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells. Mol. Cell 37, 714–727 (2010).
Moser, J. et al. Sealing of chromosomal DNA nicks during nucleotide excision repair requires XRCC1 and DNA ligase IIIα in a cell-cycle-specific manner. Mol. Cell 27, 311–323 (2007).
Gaillard, P. H. L. et al. Chromatin assembly coupled to DNA repair: a new role for chromatin assembly factor I. Cell 86, 887–896 (1996).
Polo, S. E., Roche, D. & Almouzni, G. New histone incorporation marks sites of UV repair in human cells. Cell 127, 481–493 (2006).
Ito, S. et al. XPG stabilizes TFIIH, allowing transactivation of nuclear receptors: implications for Cockayne Syndrome in XP-G/CS Patients. Mol. Cell 26, 231–243 (2007). Showed that XPG forms a stable complex with TFIIH and functions in maintaining the architecture of TFIIH, which underlines the contribution of XPG to transcription.
Coin, F. et al. Phosphorylation of XPB helicase regulates TFIIH nucleotide excision repair activity. EMBO J. 23, 4835–4846 (2004).
Hoogstraten, D. et al. Rapid switching of TFIIH between RNA polymerase I and II transcription and DNA repair in vivo. Mol. Cell 10, 1163–1174 (2002).
Iben, S. et al. TFIIH plays an essential role in RNA polymerase I transcription. Cell 109, 297–306 (2002). Found that TFIIH serves a function in ribosomal gene transcription. TFIIH is required for productive but not abortive ribosomal DNA transcription, which implies a post-initiation role for TFIIH in transcription.
Assfalg, R. et al. TFIIH is an elongation factor of RNA polymerase I. Nucleic Acids Res. 40, 650–659 (2011).
Barski, A. et al. Pol II and its associated epigenetic marks are present at Pol III-transcribed noncoding RNA genes. Nature Struct. Mol. Biol. 17, 629–634 (2010).
Oler, A. J. et al. Human RNA polymerase III transcriptomes and relationships to Pol II promoter chromatin and enhancer-binding factors. Nature Struct. Mol. Biol. 17, 620–628 (2010).
Kornberg, R. D. Eukaryotic transcriptional control. Trends Cell Biol. 9, M46–M49 (1999).
Sims, R. J. 3rd, Mandal, S. S. & Reinberg, D. Recent highlights of RNA-polymerase-II-mediated transcription. Curr. Opin. Cell Biol. 16, 263–271 (2004).
Cairns, B. R. et al. RSC, an essential, abundant chromatin-remodeling complex. Cell 87, 1249–1260 (1996).
Chao, D. M. et al. A mammalian SRB protein associated with an RNA polymerase II holoenzyme. Nature 380, 82–85 (1996).
Kim, Y. J., Bjorklund, S., Li, Y., Sayre, M. H. & Kornberg, R. D. A multiprotein mediator of transcriptional activation and its interaction with the C-terminal repeat domain of RNA polymerase II. Cell 77, 599–608 (1994).
Ossipow, V., Tassan, J. P., Nigg, E. A. & Schibler, U. A mammalian RNA polymerase II holoenzyme containing all components required for promoter-specific transcription initiation. Cell 83, 137–146 (1995).
Zawel, L. & Reinberg, D. Common themes in assembly and function of eukaryotic transcription complexes. Annu. Rev. Biochem. 64, 533–561 (1995).
Douziech, M. et al. Mechanism of promoter melting by the xeroderma pigmentosum complementation group B helicase of transcription factor IIH revealed by protein-DNA photo-cross-linking. Mol. Cell. Biol. 20, 8168–8177 (2000).
Holstege, F. C., van der Vliet, P. C. & Timmers, H. T. Opening of an RNA polymerase II promoter occurs in two distinct steps and requires the basal transcription factors IIE and IIH. EMBO J. 15, 1666–1677 (1996). Presented a model in which the crucial function of TFIIH-associated DNA helicases is to create an ssDNA region during transcription.
Coin, F., Bergmann, E., Tremeau-Bravard, A. & Egly, J. M. Mutations in XPB and XPD helicases found in xeroderma pigmentosum patients impair the transcription function of TFIIH. EMBO J. 18, 1357–1366 (1999).
Moreland, R. J. et al. A role for the TFIIH XPB DNA helicase in promoter escape by RNA polymerase II. J. Biol. Chem. 274, 22127–22130 (1999).
Dvir, A. et al. A role for ATP and TFIIH in activation of the RNA polymerase II preinitiation complex prior to transcription initiation. J. Biol. Chem. 271, 7245–7248 (1996).
Dvir, A., Conaway, R. C. & Conaway, J. W. A role for TFIIH in controlling the activity of early RNA polymerase II elongation complexes. Proc. Natl Acad. Sci. USA 94, 9006–9010 (1997).
Liu, J. et al. Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum. Cell 104, 353–363 (2001).
Lu, H., Zawel, L., Fisher, L., Egly, J. M. & Reinberg, D. Human general transcription factor IIH phosphorylates the C-terminal domain of RNA polymerase II. Nature 358, 641–645 (1992). Showed that the phosphorylation of the C-terminal domain of the largest subunit of Pol II by CDK7 contributes to the transition from transcription initiation to elongation.
Feaver, W. J., Svejstrup, J. Q., Henry, N. L. & Kornberg, R. D. Relationship of CDK-activating kinase and RNA polymerase II CTD kinase TFIIH/TFIIK. Cell 79, 1103–1109 (1994).
Shiekhattar, R. et al. Cdk-activating kinase complex is a component of human transcription factor TFIIH. Nature 374, 283–287 (1995).
Bensaude, O. et al. Regulated phosphorylation of the RNA polymerase II C-terminal domain (CTD). Biochem. Cell Biol. 77, 249–255 (1999).
Buratowski, S. Progression through the RNA polymerase II CTD cycle. Mol. Cell 36, 541–546 (2009).
Serizawa, H., Conaway, J. W. & Conaway, R. C. Phosphorylation of C-terminal domain of RNA polymerase II is not required in basal transcription. Nature 363, 371–374 (1993).
Cho, E., Tagaki, T., Moore, C. R. & Buratowski, S. mRNA capping enzyme is recruted to the transcritption complex by phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev. 11, 3319–3326 (1997).
Komarnitsky, P., Cho, E. J. & Buratowski, S. Different phosphorylated forms of RNA polymerase II and associated mRNA processing factors during transcription. Genes Dev. 14, 2452–2460 (2000).
Helenius, K. et al. Requirement of TFIIH kinase subunit Mat1 for RNA Pol II C-terminal domain Ser5 phosphorylation, transcription and mRNA turnover. Nucleic Acids Res. 39, 5025–5035 (2011).
Akoulitchev, S., Chuikov, S. & Reinberg, D. TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407, 102–106 (2000).
Yakovchuk, P., Goodrich, J. A. & Kugel, J. F. B2 RNA and Alu RNA repress transcription by disrupting contacts between RNA polymerase II and promoter DNA within assembled complexes. Proc. Natl Acad. Sci. USA 106, 5569–5574 (2009).
O'Gorman, W., Thomas, B., Kwek, K. Y., Furger, A. & Akoulitchev, A. Analysis of U1 small nuclear RNA interaction with cyclin H. J. Biol. Chem. 280, 36920–36925 (2005).
Akhtar, M. S. et al. TFIIH kinase places bivalent marks on the carboxy-terminal domain of RNA polymerase II. Mol. Cell 34, 387–393 (2009).
Glover-Cutter, K. et al. TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II. Mol. Cell. Biol. 29, 5455–5464 (2009).
Kim, M., Suh, H., Cho, E. J. & Buratowski, S. Phosphorylation of the yeast Rpb1 C-terminal domain at serines 2, 5, and 7. J. Biol. Chem. 284, 26421–26426 (2009).
Egloff, S. et al. Serine-7 of the RNA polymerase II CTD is specifically required for snRNA gene expression. Science 318, 1777–1779 (2007).
Cho, E. J., Kobor, M. S., Kim, M., Greenblatt, J. & Buratowski, S. Opposing effects of Ctk1 kinase and Fcp1 phosphatase at Ser 2 of the RNA polymerase II C-terminal domain. Genes Dev. 15, 3319–3329 (2001).
Zhou, M. et al. Tat modifies the activity of CDK9 to phosphorylate serine 5 of the RNA polymerase II carboxyl-terminal domain during human immunodeficiency virus type 1 transcription. Mol. Cell. Biol. 20, 5077–5086 (2000).
Ahn, S. H., Kim, M. & Buratowski, S. Phosphorylation of serine 2 within the RNA polymerase II C-terminal domain couples transcription and 3′ end processing. Mol. Cell 13, 67–76 (2004).
Gebara, M. M., Sayre, M. H. & Corden, J. L. Phosphorylation of the carboxy-terminal repeat domain in RNA polymerase II by cyclin-dependent kinases is sufficient to inhibit transcription. J. Cell. Biochem. 64, 390–402 (1997).
Hengartner, C. J. et al. Temporal regulation of RNA polymerase II by Srb10 and Kin28 cyclin-dependent kinases. Mol. Cell 2, 43–53 (1998).
Bonnet, F., Vigneron, M., Bensaude, O. & Dubois, M. F. Transcription-independent phosphorylation of the RNA polymerase II C-terminal domain (CTD) involves ERK kinases (MEK1/2). Nucleic Acids Res. 27, 4399–4404 (1999).
Dvir, A., Peterson, S. R., Knuth, M. W., Lu, H. & Dynan, W. S. Ku autoantigen is the regulatory component of a template-associated protein kinase that phosphorylates RNA polymerase II. Proc. Natl Acad. Sci. USA 89, 11920–11924 (1992).
Trigon, S. et al. Characterization of the residues phosphorylated in vitro by different C-terminal domain kinases. J. Biol. Chem. 273, 6769–6775 (1998).
Chambers, R. S. & Kane, C. M. Purification and characterization of an RNA polymerase II phosphatase from yeast. J. Biol. Chem. 271, 24408–24504 (1996).
Lin, P. S., Dubois, M. F. & Dahmus, M. E. TFIIF-associating carboxyl-terminal domain phosphatase dephosphorylates phosphoserines 2 and 5 of RNA polymerase II. J. Biol. Chem. 277, 45949–45956 (2002).
Mosley, A. L. et al. Rtr1 is a CTD phosphatase that regulates RNA polymerase II during the transition from serine 5 to serine 2 phosphorylation. Mol. Cell 34, 168–178 (2009).
Phatnani, H. P. & Greenleaf, A. L. Phosphorylation and functions of the RNA polymerase II CTD. Genes Dev. 20, 2922–2936 (2006).
Corden, J. L. Transcription. Seven ups the code. Science 318, 1735–1736 (2007).
Egloff, S. & Murphy, S. Cracking the RNA polymerase II CTD code. Trends Genet. 24, 280–288 (2008).
Lu, H., Fisher, R. P., Bailey, P. & Levine, A. J. The CDK7-cycH-p36 complex of transcription factor IIH phosphorylates p53, enhancing its sequence-specific DNA binding activity in vitro. Mol. Cell. Biol. 17, 5923–5934 (1997).
Xiao, H. et al. Binding of basal transcription factor TFIIH to the acidic activation domains of VP16 and p53. Mol. Cell. Biol. 14, 7013–7024 (1994).
Tong, X., Drapkin, R., Reinberg, D. & Kieff, E. The 62- and 80-kDa subunits of transcription factor IIH mediate the interaction with Epstein-Barr virus nuclear protein 2. Proc. Natl Acad. Sci. USA 92, 3259–3263 (1995).
Qadri, I., Conaway, J. W., Conaway, R. C., Schaack, J. & Siddiqui, A. Hepatitis B virus transactivator protein, HBx, associates with the components of TFIIH and stimulates the DNA helicase activity of TFIIH. Proc. Natl Acad. Sci. USA 93, 10578–10583 (1996).
Liu, J. et al. The FBP interacting repressor targets TFIIH to inhibit activated transcription. Mol. Cell 5, 331–341 (2000).
Mitchell, N. C. et al. Hfp inhibits Drosophila myc transcription and cell growth in a TFIIH/Hay-dependent manner. Development 137, 2875–2884 (2010).
Chymkowitch, P., Le May, N., Charneau, P., Compe, E. & Egly, J. M. The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. EMBO J. 30, 468–479 (2011).
Bastien, J. et al. TFIIH interacts with the retinoic acid receptor-γ and phosphorylates its AF-1-activating domain through cdk7. J. Biol. Chem. 275, 21896–21904 (2000).
Rochette-Egly, C., Adam, S., Rossignol, M., Egly, J. M. & Chambon, P. Stimulation of RARα activation function AF-1 through binding to the general transcription factor TFIIH and phosphorylation by CDK7. Cell 90, 97–107 (1997). Revealed that RARα is targeted by the CDK7 subunit of TFIIH, suggesting that the activity of a transactivator could be modulated through its interaction with a general transcription factor.
Lee, D. K., Duan, H. O. & Chang, C. From androgen receptor to the general transcription factor TFIIH. Identification of cdk activating kinase (CAK) as an androgen receptor NH2-terminal associated coactivator. J. Biol. Chem. 275, 9308–9313 (2000).
Compe, E. et al. Dysregulation of the peroxisome proliferator-activated receptor target genes by XPD mutations. Mol. Cell. Biol. 25, 6065–6076 (2005).
Compe, E. et al. Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH. Nature Neurosci. 10, 1414–1422 (2007). Reported hypomyelination in the central nervous system of mice with TTD, which is related to the dysregulation of various thyroid hormone target genes. Proposed that such a dysregulation is likely to result from the inability of the mutated TFIIH to fully participate in the recruitment of thyroid hormone receptors to their response elements.
Chen, D. et al. Activation of estrogen receptor-α by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7. Mol. Cell 6, 127–137 (2000).
Liu, Y. et al. p62, a TFIIH subunit, directly interacts with thyroid hormone receptor and enhances T3-mediated transcription. Mol. Endocrinol. 19, 879–884 (2005).
Drane, P., Compe, E., Catez, P., Chymkowitch, P. & Egly, J. M. Selective regulation of vitamin D receptor-responsive genes by TFIIH. Mol. Cell 16, 187–197 (2004).
Nigg, E. A. Cyclin-dependent kinase 7: at the cross-roads of transcription, DNA repair and cell cycle control? Curr. Opin. Cell Biol. 8, 312–317 (1996).
Morgan, D. O. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell Dev. Biol. 13, 261–291 (1997).
Schwartz, B. E., Larochelle, S., Suter, B. & Lis, J. T. Cdk7 is required for full activation of Drosophila heat shock genes and RNA polymerase II phosphorylation in vivo. Mol. Cell. Biol. 23, 6876–6886 (2003).
Larochelle, S. et al. Requirements for Cdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells. Mol. Cell 25, 839–850 (2007).
Rochette-Egly, C. Nuclear receptors: integration of multiple signalling pathways through phosphorylation. Cell Signal. 15, 355–366 (2003).
Keriel, A., Stary, A., Sarasin, A., Rochette-Egly, C. & Egly, J. M. XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARα. Cell 109, 125–135 (2002). Demonstrated that mutations in XPD result in the decreased ability of nuclear receptors to be phosphorylated by TFIIH and to stimulate expression of target genes.
Kioka, N. et al. Vinexin: a novel vinculin-binding protein with multiple SH3 domains enhances actin cytoskeletal organization. J. Cell Biol. 144, 59–69 (1999).
Bour, G., Plassat, J. L., Bauer, A., Lalevee, S. & Rochette-Egly, C. Vinexin-β interacts with the non-phosphorylated AF-1 domain of retinoid receptor-γ (RARγ) and represses RARγ-mediated transcription. J. Biol. Chem. 280, 17027–17037 (2005).
Sano, M. et al. Menage-a-trois 1 is critical for the transcriptional function of PPARγ coactivator 1. Cell. Metab. 5, 129–142 (2007).
Puigserver, P. & Spiegelman, B. M. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr. Rev. 24, 78–90 (2003).
Talukder, A. H. et al. MTA1 interacts with MAT1, a cyclin-dependent kinase-activating kinase complex ring finger factor, and regulates estrogen receptor transactivation functions. J. Biol. Chem. 278, 11676–11685 (2003).
Conaway, R. C. & Conaway, J. W. Function and regulation of the Mediator complex. Curr. Opin. Genet. Dev. 21, 225–230 (2011).
Esnault, C. et al. Mediator-dependent recruitment of TFIIH modules in preinitiation complex. Mol. Cell 31, 337–346 (2008). Reported a direct interaction between a Mediator 'head' subunit and a TFIIH core subunit and concluded that the Mediator 'head' module has a crucial role in TFIIH and TFIIE recruitment to the PIC.
Moriel-Carretero, M., Tous, C. & Aguilera, A. Control of the function of the transcription and repair factor TFIIH by the action of the cochaperone Ydj1. Proc. Natl Acad. Sci. USA 108, 15300–15305 (2011).
Manuguerra, M. et al. XRCC3 and XPD/ERCC2 single nucleotide polymorphisms and the risk of cancer: a HuGE review. Am. J. Epidemiol. 164, 297–302 (2006).
Zhang, J., Gu, S. Y., Zhang, P., Jia, Z. & Chang, J. H. ERCC2 Lys751Gln polymorphism is associated with lung cancer among Caucasians. Eur. J. Cancer 46, 2479–2484 (2010).
Le May, N. et al. TFIIH transcription factor, a target for the Rift Valley hemorrhagic fever virus. Cell 116, 541–550 (2004).
Jaitovich-Groisman, I. et al. Transcriptional regulation of the TFIIH transcription repair components XPB and XPD by the hepatitis B virus x protein in liver cells and transgenic liver tissue. J. Biol. Chem. 276, 14124–14132 (2001).
Kraemer, K. H. et al. Xeroderma pigmentosum and related disorders: examining the linkage between defective DNA repair and cancer. J. Invest. Dermatol. 103, 96S–101S (1994).
Cleaver, J. E. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nature Rev. Cancer 5, 564–573 (2005).
de Boer, J. & Hoeijmakers, J. H. Nucleotide excision repair and human syndromes. Carcinogenesis 21, 453–460 (2000).
Nance, M. A. & Berry, S. A. Cockayne syndrome: review of 140 cases. Am. J. Med. Genet. 84, 42–68 (1992).
Itin, P. H., Sarasin, A. & Pittelkow, M. R. Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes. J. Am. Acad. Dermatol. 44, 891–920 (2001).
Hashimoto, S. & Egly, J. M. Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH. Hum. Mol. Genet. 18, R224–R230 (2009).
Berneburg, M. & Lehmann, A. R. Xeroderma pigmentosum and related disorders: defects in DNA repair and transcription. Adv. Genet. 43, 71–102 (2001).
Ueda, T., Compe, E., Catez, P., Kraemer, K. H. & Egly, J. M. Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients. J. Exp. Med. 206, 3031–3046 (2009).
Botta, E. et al. Reduced level of the repair/transcription factor TFIIH in trichothiodystrophy. Hum. Mol. Genet. 11, 2919–2928 (2002). Showed that alterations in any of the gene products that result in the clinical phenotype of TTD specifically reduce the cellular content of the TFIIH complex.
de Boer, J. et al. A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy. Mol. Cell 1, 981–990 (1998).
Bergmann, E. & Egly, J. M. Trichothiodystrophy, a transcription syndrome. Trends Genet. 17, 279–286 (2001).
Takagi, Y. et al. Ubiquitin ligase activity of TFIIH and the transcriptional response to DNA damage. Mol. Cell 18, 237–243 (2005).
Frit, P. et al. Transcriptional activators stimulate DNA repair. Mol. Cell 10, 1391–1401 (2002).
Fong, Y. W. et al. A DNA repair complex functions as an oct4/sox2 coactivator in embryonic stem cells. Cell 147, 120–131 (2011). Revealed a selective co-activator role of an NER complex in transcription in the context of embryonic stem cells.
Gibbons, B. J. et al. Subunit architecture of general transcription factor TFIIH. Proc. Natl Acad. Sci. USA 109, 1949–1954 (2012).
Chang, W. H. & Kornberg, R. D. Electron crystal structure of the transcription factor and DNA repair complex, core TFIIH. Cell 102, 609–613 (2000).
Schultz, P. et al. Molecular structure of human TFIIH. Cell 102, 599–607 (2000). References 193 and 194 showed the electron crystal structure of the yeast core TFIIH and the human TFIIH complex, respectively.
Rabut, G. et al. The TFIIH subunit Tfb3 regulates cullin neddylation. Mol. Cell 43, 488–495 (2011).
Guzder, S. N., Sung, P., Prakash, L. & Prakash, S. Nucleotide excision repair in yeast is mediated by sequential assembly of repair factors and not by a pre-assembled repairosome. J. Biol. Chem. 271, 8903–8910 (1996).
Matsui, T., Segall, J., Weil, P. & Roeder, R. Multiple factors required for accurate initiation of transcription by purified RNA polymerase II. J. Biol. Chem. 255, 11992–11996 (1980).
Samuels, M., Fire, A. & Sharp, P. A. Separation and characterization of factors mediating accurate transcription by RNA polymerase II. J. Biol. Chem. 257, 14419–14427 (1982).
Sawadogo, M. & Roeder, R. Interaction of a gene-specific transcription factor with the adenovirus major late promoter upstream of the TATA box region. Cell 43, 165–175 (1985).
Reinberg, D. & Roeder, R. G. Factors involved in specific transcription by mammalian RNA polymerase II. Purification and functional analysis of initiation factors IIB and IIE. J. Biol. Chem. 262, 3310–3321 (1987).
Buratowski, S., Hahn, S., Guarente, L. & Sharp, P. A. Five intermediate complexes in transcription initiation by RNA polymerase II. Cell 56, 549–561 (1989).
Conaway, J. W., Hanley, J. P., Garrett, K. P. & Conaway, R. C. Transcription initiated by RNA polymerase II and transcription factors from liver. Structure and action of transcription factors epsilon and tau. J. Biol. Chem. 266, 7804–7811 (1991).
Perissi, V. & Rosenfeld, M. G. Controlling nuclear receptors: the circular logic of cofactor cycles. Nature Rev. Mol. Cell Biol. 6, 542–554 (2005).
The authors thank all of their past and present associates who have participated to the TFIIH adventure. The authors especially would like to thank R. Conaway and H. Naegeli for critical reading of the manuscript and F. Coin for helpful discussions. The authors apologize to all their colleagues whose important findings could not be included in this Review because of space limitations. This study was supported by a European Research Council advanced grant, the Agence Nationale de la Recherche (N#ANR-08MIEN-022-03), the Association pour la Recherche sur le Cancer and the Institut National du Cancer (INCA-2008-041). E.C. and J.M.E. are supported by the Institut National de la Santé et de la Recherche Médicale.
The authors declare no competing financial interests.
- Nucleotide excision repair
(NER). The repair pathway that is used to remove the vast majority of lesions that are located on a DNA single strand, including lesions caused by ultraviolet (UV) light and cisplatin damage.
Enzymes that move directionally along a nucleic acid phosphodiester backbone and separate two annealed nucleic acid strands by using energy derived from ATP hydrolysis.
- Transfer RNAs
(tRNAs). The ribonucleic acids that transport specific amino acids to the ribosome for incorporation into the growing polypeptide chain.
- Ribosomal RNA
(rRNA). The ribonucleic acid element of the ribosome, which orchestrates protein synthesis.
- Small nuclear RNAs
(snRNAs). Small ribonucleic acids, which are located in the nucleus and are involved in different molecular processes such as transcriptional regulation and RNA splicing.
(miRNAs). Short ribonucleic acids that are post-transcriptional regulators able to recognize complementary sequences on target mRNA transcripts.
- Spliceosomal snRNAs
Small ribonucleic acids that participate in the removal of introns from pre-mRNA.
- Nuclear receptors
Ligand-dependent and -independent transcription factors that are highly conserved evolutionarily from invertebrates to higher organisms. The nuclear receptor superfamily includes receptors for thyroid and steroid hormones, retinoids and vitamin D, as well as 'orphan' receptors of unknown ligands.
- Ubiquitin–proteasome machinery
A selective system of protein degradation. This first requires the ubiquitin conjugation of the target protein via three types of enzymes: E1 (ubiquitin-activation enzyme), E2 (ubiquitin-conjugation enzyme) and E3 (ubiquitin ligase). Polyubiquitylated substrates are then recognized and degraded by the 26S proteasome in an ATP-dependent manner.
About this article
Cite this article
Compe, E., Egly, JM. TFIIH: when transcription met DNA repair. Nat Rev Mol Cell Biol 13, 343–354 (2012). https://doi.org/10.1038/nrm3350
Cellular and Molecular Life Sciences (2022)
Nature Communications (2021)
Ribosomal protein S3 associates with the TFIIH complex and positively regulates nucleotide excision repair
Cellular and Molecular Life Sciences (2021)
CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer
Journal of Hematology & Oncology (2020)
Genome Biology (2020)