The Transcription/DNA Repair Factor TFIIH

Laura Radu, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Cedex, France
Anne Maglott‐Roth, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Cedex, France
Arnaud Poterszman, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Cedex, France

Published online: February 2013

DOI: 10.1002/9780470015902.a0024192

Transcription factor IIH (TFIIH) is a eukaryotic multicomponent macromolecular assembly composed of 10 subunits including two deoxyribonucleic acid (DNA)-dependent helicase activities of opposite polarities and a kinase. Mutations in the helicases xeroderma pigmentosum group D protein (XPD) and xeroderma pigmentosum group B protein (XPB) as well as in the p8/TTD-A subunit of human TFIIH are associated with three dramatic genetic disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). Initially recognised as a basal factor responsible for transcription initiation of protein coding genes and transition from initiation to elongation, TFIIH also plays a critical role in nucleotide excision repair via its DNA-opening helicase activity at the site of a lesion. A subcomplex, harbouring its kinase activity, phosphorylates the carboxy-terminal domain (CTD) of ribonucleic acid (RNA) polymerase II as well as a number of transcription regulators including nuclear hormone receptors.

Key Concepts:

  • TFIIH is a prime example of multienzyme multitasking macromolecular assembly. Recent data suggest that several components are found in nonTFIIH complexes and that the function of TFIIH is regulated by its subunit composition.
  • The human transcription/DNA repair factor TFIIH is a multi-subunit complex composed two functional and structural entities: core-TFIIH consists of XPB, p62, p52, p44, p34 and p8, whereas the CDK-activating kinase (CAK) subcomplex contains cyclin-dependent kinase 7 (CDK7), cyclin H and MAT1. XPD bridges the core-TFIIH to the CDK activating kinase (CAK) complex, which also exists as a free complex with a distinct function.
  • Although identified as a basal factor responsible for transcription initiation, TFIIH also plays a critical role in nucleotide excision repair and is implicated in the control of cell cycle progression.
  • Key insights into TFIIH result from investigations centred on the analysis of mutations identified in XP, CS and TTD patients.
  • Most mutations identified in patients reside within the noncatalytic regions of the helicases and do not affect the enzymatic activity of TFIIH per se but rather disturb the interactions of the catalytic subunits with their regulatory partners, impairing transcription and DNA repair.

Keywords: transcription; DNA repair; helicase; xeroderma pigmentosum; trichothiodystrophy

Figure 1. TFIIH: a multisubunit/multienzymatic complex. Human TFIIH is a 10-subunit complex composed of a core (in green: p62, p52, p44, p34 and TTDA) associated to the CAK (in orange: Cdk7, CyclH and MAT1) and two helicase subunits: XPB (in light blue) and XPD (in magenta). TFIIH harbours two helicases of opposite polarity XPB and XPD and a kinase Cdk7. The XPG endonuclease (in dark blue) is often found associated with TFIIH and triggers dual incision and excision of the protein-free damaged oligonucleotide. p44 has been described as an E3 ubiquitin ligase in yeast.
Figure 2. Domain structures of TFIIH subunits. Diagrams illustrating the organisation of TFIIH subunits. Human/Yeast nomenclature of each subunit is indicated on the right. The different domains of the core subunits are represented in different green and those of CAK are in orange. The two helicase subunits XPB and XPD are represented in blue and in magenta, respectively. The seven conserved helicases motifs are represented in black.
Figure 3. TFIIH a multitask complex. The TFIIH complex is involved both in RNPII-dependant transcription and in NER. In RNA Polymerase II-dependant transcription, TFIIH opens DNA around the promoter and phosphorylates the CTD of the RNA Polymerase II (light blue) to licence transcription. In NER, TFIIH opens DNA around the lesion. XPC-HR23B recognises the damaged DNA and interacts with TFIIH. XPB and XPD helicases open the DNA around the lesion, allowing the stable association of XPA and RPA. The arrival of XPG and XPF-ERCC1 triggers dual incision and excision of the protein-free damaged oligonucleotide.
Figure 4. Crystal structures of XPB and XPD archaeal orthologues. XPB homologue of Archaeoglobus fulgidus (pdb 2FWR) and XPD homologue of Sulfolobus acidocaldarius (pdb 3CRV) folds are shown as ribbons and mesh. The helicase domains of AfXPB are coloured in blue. The damage recognition domain (DRD), the ThM (Thumb) and the RED (contains a conserved R-E-D motif) domains are highlighted. SaXPD is coloured in purple except for the FeS domain and the ARCH domain which are highlighted in magenta.
Figure 5. TFIIH mutations and genetic disorders. Schematic representation of XPB (blue), XPD (magenta) and p8/TTD-A (green) subunits. XP/TTD mutation sites on p8/TTDA, XPB and XPD gene. Mutations found in XP (black) and XP/CS (red) patients are represented above the corresponding sequence, mutations found in TTD patients are indicated below. Ribbon and mesh representation of p8/TTD-A yeast homologue (green) in complex with the C-terminal domain of p52/Tfb2 (light green, pdb 3DOM). TTD mutations L21P and R56X (premature stop codon) are mapped onto the structure.
close
 References
    Aguilar-Fuentes J, Valadez-Graham V, Reynaud E and Zurita M (2006) TFIIH trafficking and its nuclear assembly during early Drosophila embryo development. Journal of Cell Science 119(Pt 18): 3866–3875.
    Aguilar-Fuentes J, Fregoso M, Herrera M et al. (2008) p8/TTDA overexpression enhances UV-irradiation resistance and suppresses TFIIH mutations in a Drosophila trichothiodystrophy model. PLoS Genetics 4(11): e1000253.
    Araujo SJ, Tirode F, Coin F et al. (2000) 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 and Development 14(3): 349–359.
    Bernardes de Jesus BM, Bjoras M, Coin F and Egly JM (2008) Dissection of the molecular defects caused by pathogenic mutations in the DNA repair factor XPC. Molecular and Cellular Biology 28(23): 7225–7235.
    Botta E, Nardo T, Lehmann AR et al. (2002) Reduced level of the repair/transcription factor TFIIH in trichothiodystrophy. Human Molecular Genetics 11(23): 2919–2928.
    Busso D, Keriel A, Sandrock B et al. (2000) Distinct regions of MAT1 regulate cdk7 kinase and TFIIH transcription activities. Journal of Biological Chemistry 275(30): 22815–22823.
    Chang WH and Kornberg RD (2000) Electron crystal structure of the transcription factor and DNA repair complex, core TFIIH. Cell 102(5): 609–613.
    Chen J, Larochelle S, Li X and Suter B (2003) Xpd/Ercc2 regulates CAK activity and mitotic progression. Nature 424(6945): 228–232.
    Coin F, Oksenych V and Egly JM (2007) Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair. Molecular Cell 26(2): 245–256.
    Coin F, Oksenych V, Mocquet V et al. (2008) Nucleotide excision repair driven by the dissociation of CAK from TFIIH. Molecular Cell 31(1): 9–20.
    Coin F, Proietti De Santis L, Nardo T et al. (2006) p8/TTD-A as a repair-specific TFIIH subunit. Molecular Cell 21(2): 215–226.
    Dubaele S, Proietti De Santis L, Bienstock RJ et al. (2003) Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients. Molecular Cell 11(6): 1635–1646.
    Dvir A, Conaway JW and Conaway RC (2001) Mechanism of transcription initiation and promoter escape by RNA polymerase II. Current Opinion in Genetics and Development 11(2): 209–214.
    Fan L, Arvai AS, Cooper PK et al. (2006) Conserved XPB core structure and motifs for DNA unwinding: implications for pathway selection of transcription or excision repair. Molecular Cell 22(1): 27–37.
    Fan L, Fuss JO, Cheng QJ et al. (2008) XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations. Cell 133(5): 789–800.
    Fribourg S, Kellenberger E, Rogniaux H et al. (2000) Structural characterization of the cysteine-rich domain of TFIIH p44 subunit. Journal of Biological Chemistry 275(41): 31963–31971.
    Gerard M, Fischer L, Moncollin V et al. (1991) Purification and interaction properties of the human RNA polymerase B (II) general transcription factor BTF2. Journal of Biological Chemistry 266(31): 20940–20945.
    Gervais V, Busso D, Wasielewski E et al. (2001) Solution structure of the N-terminal domain of the human TFIIH MAT1 subunit: new insights into the RING finger family. Journal of Biological Chemistry 276(10): 7457–7464.
    Gervais V, Lamour V, Jawhari A et al. (2004) TFIIH contains a PH domain involved in DNA nucleotide excision repair. Nature Structural and Molecular Biology 11(7): 616–622.
    Gibbons BJ, Brignole EJ, Azubel M et al. (2012) Subunit architecture of general transcription factor TFIIH. Proceedings of the National Academy of Sciences of the USA 109(6): 1949–1954.
    Giglia-Mari G, Miquel C, Theil AF et al. (2006) Dynamic interaction of TTDA with TFIIH is stabilized by nucleotide excision repair in living cells. PLoS Biology 4(6): e156.
    Giglia-Mari G, Coin F, Ranish JA et al. (2004) A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A. Nature Genetics 36(7): 714–719.
    Grunberg S, Warfield L and Hahn S (2012) Architecture of the RNA polymerase II preinitiation complex and mechanism of ATP-dependent promoter opening. Nature Structural and Molecular Biology 19(8): 788–796.
    Guzder SN, Sung P, Bailly V, Prakash L and Prakash S (1994) RAD25 is a DNA helicase required for DNA repair and RNA polymerase II transcription. Nature 369(6481): 578–581.
    Ito S, Kuraoka I, Chymkowitch P et al. (2007) XPG stabilizes TFIIH, allowing transactivation of nuclear receptors: implications for Cockayne syndrome in XP-G/CS patients. Molecular Cell 26(2): 231–243.
    Ito S, Tan LJ, Andoh D et al. (2010) MMXD, a TFIIH-independent XPD–MMS19 protein complex involved in chromosome segregation. Molecular Cell 39(4): 632–640.
    Jawhari A, Laine JP, Dubaele S et al. (2002) p52 Mediates XPB function within the transcription/repair factor TFIIH. Journal of Biological Chemistry 277(35): 31761–31767.
    Jawhari A, Boussert S, Lamour V et al. (2004) Domain architecture of the p62 subunit from the human transcription/repair factor TFIIH deduced by limited proteolysis and mass spectrometry analysis. Biochemistry 43(45): 14420–14430.
    Kainov DE, Vitorino M, Cavarelli J, Poterszman A and Egly JM (2008) Structural basis for group A trichothiodystrophy. Nature Structural and Molecular Biology 15(9): 980–984.
    Kim TK, Ebright RH and Reinberg D (2000) Mechanism of ATP-dependent promoter melting by transcription factor IIH. Science 288(5470): 1418–1422.
    Kuper J, Wolski SC, Michels G and Kisker C (2011) Functional and structural studies of the nucleotide excision repair helicase XPD suggest a polarity for DNA translocation. EMBO Journal 31(2): 494–502.
    Lafrance-Vanasse J, Arseneault G, Cappadocia L et al. (2012) Structural and functional characterization of interactions involving the Tfb1 subunit of TFIIH and the NER factor Rad2. Nucleic Acids Research 40(12): 5739–5750.
    Lee JH, Jung HS and Gunzl A (2009) Transcriptionally active TFIIH of the early diverged eukaryote Trypanosoma brucei harbors two novel core subunits but not a cyclin-activating kinase complex. Nucleic Acids Research 37(11): 3811–3820.
    Lee SK, Yu SL, Prakash L and Prakash S (2002) Requirement of yeast RAD2, a homolog of human XPG gene, for efficient RNA polymerase II transcription. Implications for Cockayne syndrome. Cell 109(7): 823–834.
    Li X, Urwyler O and Suter B (2010) Drosophila Xpd regulates Cdk7 localization, mitotic kinase activity, spindle dynamics, and chromosome segregation. PLoS Genetics 6(3): e1000876.
    Lin YC, Choi WS and Gralla JD (2005) TFIIH XPB mutants suggest a unified bacterial-like mechanism for promoter opening but not escape. Nature Structural and Molecular Biology 12(7): 603–607.
    Liu H, Rudolf J, Johnson KA et al. (2008) Structure of the DNA repair helicase XPD. Cell 133(5): 801–812.
    Lu H, Zawel L, Fisher L, Egly JM and Reinberg D (1992) Human general transcription factor IIH phosphorylates the C-terminal domain of RNA polymerase II. Nature 358(6388): 641–645.
    Oksenych V, Bernardes de Jesus B, Zhovmer A, Egly JM and Coin F (2009) Molecular insights into the recruitment of TFIIH to sites of DNA damage. EMBO Journal 28(19): 2971–2980.
    Rabut G, Le Dez G, Verma R et al. (2011) The TFIIH subunit Tfb3 regulates cullin neddylation. Molecular Cell 43(3): 488–495.
    Ranish JA, Hahn S, Lu Y et al. (2004) Identification of TFB5, a new component of general transcription and DNA repair factor IIH. Nature Genetics 36(7): 707–713.
    Rochette-Egly C (2005) Dynamic combinatorial networks in nuclear receptor-mediated transcription. Journal of Biological Chemistry 280(38): 32565–32568.
    Schaeffer L, Roy R, Humbert S et al. (1993) DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science 260(5104): 58–63.
    Schaeffer L, Moncollin V, Roy R et al. (1994) The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. EMBO Journal 13(10): 2388–2392.
    Schultz P, Fribourg S, Poterszman A et al. (2000) Molecular structure of human TFIIH. Cell 102(5): 599–607.
    Serizawa H, Conaway RC and Conaway JW (1993) Multifunctional RNA polymerase II initiation factor delta from rat liver. Relationship between carboxyl-terminal domain kinase, ATPase, and DNA helicase activities. Journal of Biological Chemistry 268(23): 17300–17308.
    Takagi Y, Masuda CA, Chang WH et al. (2005) Ubiquitin ligase activity of TFIIH and the transcriptional response to DNA damage. Molecular Cell 18(2): 237–243.
    Ueda T, Compe E, Catez P, Kraemer KH and Egly JM (2009) Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients. Journal of Experimental Medicine 206(13): 3031–3046.
    Wang Z, Svejstrup JQ, Feaver WJ et al. (1994) Transcription factor b (TFIIH) is required during nucleotide-excision repair in yeast. Nature 368(6466): 74–76.
    Wolski SC, Kuper J, Hanzelmann P et al. (2008) Crystal structure of the FeS cluster-containing nucleotide excision repair helicase XPD. PLoS Biology 6(6): e149.
    Yudkovsky N, Ranish JA and Hahn S (2000) A transcription reinitiation intermediate that is stabilized by activator. Nature 408(6809): 225–229.
 Further Reading
    Compe E and Egly JM (2012) TFIIH: when transcription met DNA repair. Nature Reviews Molecular Cell Biology 13(6): 343–354.
    Fisher RP (2005) Secrets of a double agent: CDK7 in cell-cycle control and transcription. Journal of Cell Science 118(Pt 22): 5171–5180.
    Friedberg EC, Aguilera A, Gellert M et al. (2006) DNA repair: from molecular mechanism to human disease. DNA Repair 5(8): 986–996.
    Fuss JO and Tainer JA (2011) XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase. DNA Repair 10(7): 697–713.
    Singleton MR, Dillingham MS and Wigley DB (2007) Structure and mechanism of helicases and nucleic acid translocases. Annual Review of Biochemistry 76: 23–50.
    Stefanini M, Botta E, Lanzafame M and Orioli D (2010) Trichothiodystrophy: from basic mechanisms to clinical implications. DNA Repair 9(1): 2–10.

Related Sub-Topics:

Protein Structure | Nucleic Acid Structure | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | DNA Damage and Repair
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: The Transcription/DNA Repair Factor TFIIH
 
How to Cite close
Radu, Laura, Maglott‐Roth, Anne, and Poterszman, Arnaud(Feb 2013) The Transcription/DNA Repair Factor TFIIH. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024192]