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Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH

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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Figure 1: Dysregulation of thyroid hormone target genes in TTD brain.
Figure 2: Defective recruitment of TRs on the promoter of thyroid hormone target genes in TTD.
Figure 3: TFIIH promotes the TR recruitment on the MBP promoter.
Figure 4: Limiting amount of TFIIH in TTD cells affects the transactivation by TR.
Figure 5: TFIIH mutations affect the TR recruitment.

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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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Correspondence to Emiliana Borrelli or Jean-Marc Egly.

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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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