Abstract
Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH yield the rare genetic disorder trichothiodystrophy (TTD). Although this syndrome was initially associated with a DNA repair defect, individuals with TTD develop neurological features, such as microcephaly and hypomyelination that could be connected to transcriptional defects. Here we show that an XPD mutation in TTD mice results in a spatial and selective deregulation of thyroid hormone target genes in the brain. Molecular analyses performed on the mice brain tissue demonstrate that TFIIH is required for the stabilization of thyroid hormone receptors (TR) to their DNA-responsive elements. The limiting amounts of TFIIH found in individuals with TTD thus contribute to the deregulation of TR-responsive genes. The discovery of an unexpected stabilizing function for TFIIH deepens our understanding of the pathogenesis and neurological manifestations observed in TTD individuals.
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Acknowledgements
We thank C. Laurent, H. Dréau and M. Bouhadjar for the three-dimensional imaging. C. Braun and Ph. Catez for their technical expertise, Y. Schwab for TEM, I. Kolb-Cheynel for the production of recombinant proteins, M. Plateroti for the TRα1 antibodies, and J. Samarut and N. LeMy for discussions. This work was supported by grants from the Association pour la Recherche sur le Cancer (04-2-3113), the Agence Nationale de Recherche (ANR-05-MRAR-005-01), the European Community (MRTM-CT-2003-503618), the ACI Biologie Cellulaire et Structurale (3-2-535), the Institut des Maladies Rares (A03098MS) and the Commissariat à l'Energie Atomique.
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E.C., M.M., E.B. and J.-M.E. conceived and designed the experiments. E.C., M.M. and L.S. carried out the experiments. E.C., M.M., L.S., J.M., E.B. and J.-M.E. analyzed the data. E.B., J.M. and J.-M.E. contributed reagents, materials and analysis tools. E.C., E.B. and J.-M.E. wrote the paper.
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Compe, E., Malerba, M., Soler, L. et al. Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH. Nat Neurosci 10, 1414–1422 (2007). https://doi.org/10.1038/nn1990
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DOI: https://doi.org/10.1038/nn1990
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