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Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder

Nature Genetics volume 26, pages 307–313 (2000)Cite this article

Abstract

The repair-deficient form of trichothiodystrophy (TTD) most often results from mutations in the genes XPB or XPD, encoding helicases of the transcription/repair factor TFIIH. The genetic defect in a third group, TTD-A, is unknown, but is also caused by dysfunctioning TFIIH. None of the TFIIH subunits carry a mutation and TFIIH from TTD-A cells is active in both transcription and repair. Instead, immunoblot and immunofluorescence analyses reveal a strong reduction in the TFIIH concentration. Thus, the phenotype of TTD-A appears to result from sublimiting amounts of TFIIH, probably due to a mutation in a gene determining the complex stability. The reduction of TFIIH mainly affects its repair function and hardly influences transcription.

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Figure 1: Repair, transcription and correction of repair defect in TTD-A fibroblasts.
Figure 2: Transcription and repair activities of TFIIH from fibroblasts.
Figure 3: Reduced concentration of TFIIH subunits in the TTDA whole cell extract.
Figure 4: Reduced concentrations of TFIIH in TTD-A fibroblasts as apparent from immunofluorescence.
Figure 5: IIH/TTD-A restores NER in TTD-A.
Figure 6: Northern-blot analysis.

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Acknowledgements

We thank D. Bootsma for support; F. Coin, N.G.J. Jaspers, A. Lehman, M. Stefanini, G.S. Winkler and G. Weeda for discussions; A. Fery and J.L. Weickert for technical assistance; A. Raams for cell culture; and S. Vicaire for DNA sequencing. E.B. was supported by a Ligue Nationale Contre le Cancer fellowship, J.A. by la Fondation pour la Recherche Médicale. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpital Universitaire de Strasbourg, by HFSP and EEC grants to both J.M.E. and J.H.J.H., the Association pour la Recherche sur le Cancer, by the Dutch Cancer Society, a NIH programme to J.H.J.H., the Research Institute for Diseases in the Elderly, funded by the Ministry of Education & Science and the Ministry of Health, Welfare and Sports, through the Netherlands Organization for Scientific Research (NWO) and the Louis Jeantet Foundation.

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  1. Wim Vermeulen and Etienne Bergmann: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology and Genetics, Medical Genetics Center, Erasmus University, Rotterdam, The Netherlands

    Wim Vermeulen, Suzanne Rademakers, Esther Appeldoorn & Jan H.J. Hoeijmakers

  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, Strasbourg, France

    Etienne Bergmann, Jérôme Auriol, Philippe Frit & Jean-Marc Egly

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Correspondence to Jan H.J. Hoeijmakers or Jean-Marc Egly.

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Vermeulen, W., Bergmann, E., Auriol, J. et al. Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder. Nat Genet 26, 307–313 (2000). https://doi.org/10.1038/81603

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