The Transcription/DNA Repair Factor TFIIH


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 (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.



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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.

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Radu, Laura, Maglott‐Roth, Anne, and Poterszman, Arnaud(Feb 2013) The Transcription/DNA Repair Factor TFIIH. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024192]