A temperature-sensitive disorder in basal transcription and DNA repair in humans


The xeroderma pigmentosum group D (XPD) helicase subunit of TFIIH functions in DNA repair and transcription initiation1,2. Different mutations in XPD give rise to three ultraviolet-sensitive syndromes: the skin cancer-prone disorder xeroderma pigmentosum (XP), in which repair of ultraviolet damage is affected; and the severe neurodevelopmental conditions Cockayne syndrome (CS) and trichothiodystrophy (TTD). In the latter two, the basal transcription function of TFIIH is also presumed to be affected3,4,5. Here we report four unusual TTD patients with fever-dependent reversible deterioration of TTD features such as brittle hair. Cells from these patients show an in vivo temperature-sensitive defect of transcription and DNA repair due to thermo-instability of TFIIH. Our findings reveal the clinical consequences of impaired basal transcription and mutations in very fundamental processes in humans, which previously were only known in lower organisms.

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Figure 1: Clinical characteristics of patients TTD1RO and TTD1DOD.
Figure 2: DNA repair characteristics and XPD defect of TTD1RO and TTD1DOD.
Figure 3: DNA repair properties and TFIIH defect in TTD1RO-SV.
Figure 4: Effect of temperature increase on transcription, repair, TFIIH and survival in TTD1RO cells.


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We thank D. Bootsma and F.A. Beemer for support; M. Stefanini for discussions; and J.-M. Egly for materials. This work was supported by the Dutch Cancer Society, EEC, NIH, 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), a SPINOZA award and the Louis Jeantet Foundation.

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Correspondence to Jan H.J. Hoeijmakers.

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Vermeulen, W., Rademakers, S., Jaspers, N. et al. A temperature-sensitive disorder in basal transcription and DNA repair in humans. Nat Genet 27, 299–303 (2001). https://doi.org/10.1038/85864

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