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TFIIH contains a PH domain involved in DNA nucleotide excision repair

Nature Structural & Molecular Biology volume 11, pages 616–622 (2004)Cite this article

Abstract

The human general transcription factor TFIIH is involved in both transcription and DNA repair. We have identified a structural domain in the core subunit of TFIIH, p62, which is absolutely required for DNA repair activity through the nucleotide excision repair pathway. Using coimmunoprecipitation experiments, we showed that this activity involves the interaction between the N-terminal domain of p62 and the 3′ endonuclease XPG, a major component of the nucleotide excision repair machinery. Furthermore, we reconstituted a functional TFIIH particle with a mutant of p62 lacking the N-terminal domain, showing that this domain is not required for assembly of the TFIIH complex and basal transcription. We solved its three-dimensional structure and found an unpredicted pleckstrin homology and phosphotyrosine binding (PH/PTB) domain, uncovering a new class of activity for this fold.

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Figure 1: Three-dimensional structure of the N-terminal domain of p62 (residues 1–108).
Figure 2: Structure-guided sequence alignment of the N-terminal domain of human (Homo sapiens) p62 with orthologous sequences and selected PH/PTB domains.
Figure 3: Structural comparison of PH and PTB domains and molecular surface properties of p62(1–108).
Figure 4: Deletion of p62(1–108) impairs the NER activity of TFIIH.
Figure 5: p62(1–108) interacts with the endonuclease XPG.

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Acknowledgements

This work was supported by funds from the Université Louis Pasteur de Strasbourg, the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale and SPINE (contract QLG2-CT-2002-00988). V.G. was supported by a grant from ADRERUS/LILLY and by the Ministère de la Recherche et de l'Enseignement Supérieur and A.J. by the Association pour la Recherche contre le Cancer. We express our gratitude to D. Moras for constant support and fruitful discussions. We wish to acknowledge A. Milon at the IPBS in Toulouse for his hospitality during structure calculations. I. Kolb and J.L. Weickert are acknowledged for insect cell production. We are grateful to C. Ling for the management of the computing and NMR facilities and to R.A. Atkinson for critical reading of the manuscript.

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Author notes

  1. Virginie Gervais

    Present address: Institut de Pharmacologie et de Biologie Structurale, 205 Rte de Narbonne, 31077, Toulouse Cedex, France

  2. Valérie Lamour

    Present address: Rockefeller University, 1230 York Avenue, New York, New York, 10021-6399, USA

  3. Virginie Gervais, Valérie Lamour and Anass Jawhari: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104, 1 Rue Laurent Fries, BP 10142, Illkirch, 67404, Cedex, France

    Virginie Gervais, Valérie Lamour, Anass Jawhari, Florent Frindel, Emeric Wasielewski, Sandy Dubaele, Jean-Marc Egly, Jean-Claude Thierry, Bruno Kieffer & Arnaud Poterszman

  2. Institut de Pharmacologie et de Biologie Structurale, 205 Rte de Narbonne, 31077, Toulouse Cedex, France

    Valérie Lamour

  3. Rockefeller University, 1230 York Avenue, New York, New York, 10021-6399, USA

    Virginie Gervais

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Supplementary information

Supplementary Fig. 1

Secondary structure elements of p62(1–108). (PDF 34 kb)

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Gervais, V., Lamour, V., Jawhari, A. et al. TFIIH contains a PH domain involved in DNA nucleotide excision repair. Nat Struct Mol Biol 11, 616–622 (2004). https://doi.org/10.1038/nsmb782

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