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TFIIH: when transcription met DNA repair

An Erratum to this article was published on 01 June 2012

This article has been updated

Key Points

  • 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.

Abstract

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'.

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Figure 1: TFIIH opens DNA to allow the incision and excision of damaged oligonucleotides.
Figure 2: TFIIH is an essential factor of transcription initiation.

Change history

  • 01 June 2012

    There was an error in table 1 on page 345 of this article: XPD is a 5' to 3' ATP-dependent helicase and not a 3' to 5' ATP-dependent helicase. This has been corrected online. We apologize for any confusion caused to readers.

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Acknowledgements

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.

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Glossary

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.

Helicases

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.

MicroRNAs

(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.

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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

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