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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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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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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DOI: https://doi.org/10.1038/81603
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