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Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH

Nature Genetics volume 20, pages 184–188 (1998)Cite this article

Abstract

In most cases, xeroderma pigmentosum group D (XP-D) and trichothiodystrophy (TTD) patients carry mutations in the carboxy-terminal domain of the evolutionarily conserved helicase XPD, which is one of the subunits of the transcription/repair factor TFIIH (Refs 1,2). In this study, we demonstrate that XPD interacts specifically with p44, another subunit of TFIIH, and that this interaction results in the stimulation of 5´→3´ helicase activity. Mutations in the XPD C-terminal domain, as found in most patients, prevent the interaction with p44, thus explaining the decrease in XPD helicase activity and the nucleotide excision repair (NER) defect.

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Figure 1: Highly purified TFIIH exhibits 5´→3´ helicase activity.
Figure 2: HeLa TFIIH (Hep HPLC) was dialysed against buffer containing either 0.05 or 1.20 M KCl before immunoprecipitation with Ab-XPD.
Figure 3: p44 interacts with and stimulates XPD helicase activity via its N terminus.
Figure 4: Mutations in the C-terminal domain of XPD abolish the interaction with p44.

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Acknowledgements

We wish to express our gratitude to J.H.J. Hoeijmakers, D. Moras, A. Poterszman, A. Sarasin and J.-C. Thierry for fruitful discussions, B. Bell and F.J. Dilworth for critical reading of the manuscript, J.R. Hwang for p44 mutant constructs, I. Kolb for production of recombinant in baculovirus expression system and A. Fery for her excellent technical expertise. This work was supported by grants from the Ministère de la Recherche et de l'Enseignement Supérieur (F.C. and S.F.), by the Association pour la Recherche sur le Cancer (J.C.M.), by the Human Frontier Grant, by The Hopitaux Universitaires de Strasbourg and the Telethon Grant E.550.

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  1. Frédéric Coin, Jean-Christophe Marinoni, Sébastien Fribourg and Jean-Marc Egly: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, B.P.163, 67404 Illkirch CedexC.U. de Strasbourg France.F.C. and J.-C.M. contributed equally to this work.

Authors and Affiliations

  1. Istituto di Genetica Biochimica ed Evoluzionistica, CNR Via Abbiategrasso, 207, Pavia, 27100, Italy

    Carlo Rodolfo, Antonia Maria Pedrini & Jean-Marc Egly

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  1. Frédéric Coin
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Correspondence to Jean-Marc Egly.

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Coin, F., Marinoni, JC., Rodolfo, C. et al. Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH. Nat Genet 20, 184–188 (1998). https://doi.org/10.1038/2491

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