title: Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality.
abstract: The ten-subunit transcription factor IIH (TFIIH) plays a crucial role in transcription and nucleotide excision repair (NER). Inactivating mutations in the smallest 8-kDa TFB5/TTDA subunit cause the neurodevelopmental progeroid repair syndrome trichothiodystrophy A (TTD-A). Previous studies have shown that TTDA is the only TFIIH subunit that appears not to be essential for NER, transcription, or viability. We studied the consequences of TTDA inactivation by generating a Ttda knock-out (Ttda(-/-) ) mouse-model resembling TTD-A patients. Unexpectedly, Ttda(-/-) mice were embryonic lethal. However, in contrast to full disruption of all other TFIIH subunits, viability of Ttda(-/-) cells was not affected. Surprisingly, Ttda(-/-) cells were completely NER deficient, contrary to the incomplete NER deficiency of TTD-A patient-derived cells. We further showed that TTD-A patient mutations only partially inactivate TTDA function, explaining the relatively mild repair phenotype of TTD-A cells. Moreover, Ttda(-/-) cells were also highly sensitive to oxidizing agents. These findings reveal an essential role of TTDA for life, nucleotide excision repair, and oxidative DNA damage repair and identify Ttda(-/-) cells as a unique class of TFIIH mutants.
authors: Department of Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors: Arjan F
authors: AF
authors: Theil
authors: Julie
authors: J
authors: Nonnekens
authors: Barbara
authors: B
authors: Steurer
authors: Pierre-Olivier
authors: PO
authors: Mari
authors: Jan
authors: J
authors: de Wit
authors: Charlène
authors: C
authors: Lemaitre
authors: Jurgen A
authors: JA
authors: Marteijn
authors: Anja
authors: A
authors: Raams
authors: Alex
authors: A
authors: Maas
authors: Marcel
authors: M
authors: Vermeij
authors: Jeroen
authors: J
authors: Essers
authors: Jan H J
authors: JH
authors: Hoeijmakers
authors: Giuseppina
authors: G
authors: Giglia-Mari
authors: Wim
authors: W
authors: Vermeulen
mesh_terms: D000818:Animals; D003057:Cockayne Syndrome; D004260:DNA Repair; D006801:Humans; D009154:Mutation; D051758:Transcription Factor TFIIH / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D054463:Trichothiodystrophy Syndromes / Q000235:genetics
chemical_list: D014157:Transcription Factors; D051758:Transcription Factor TFIIH
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