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- Title
Disruption of TTDA Results in Complete Nucleotide Excision Repair Deficiency and Embryonic Lethality.
- Authors
Theil, Arjan F.; Nonnekens, Julie; Steurer, Barbara; Mari, Pierre-Olivier; de Wit, Jan; Lemaitre, Charlène; Marteijn, Jurgen A.; Raams, Anja; Maas, Alex; Vermeij, Marcel; Essers, Jeroen; Hoeijmakers, Jan H. J.; Giglia-Mari, Giuseppina; Vermeulen, Wim
- 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 knockout (Ttda2/2) mouse-model resembling TTD-A patients. Unexpectedly, Ttda2/2mice were embryonic lethal. However, in contrast to full disruption of all other TFIIH subunits, viability of Ttda2/2cells was not affected. Surprisingly, Ttda2/2cells 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, Ttda2/2cells 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 Ttda2/2cells as a unique class of TFIIH mutants.
- Subjects
TRANSCRIPTION factors; DNA damage; CELLS; NUCLEIC acids; BIOCHEMICAL genetics
- Publication
PLoS Genetics, 2013, Vol 9, Issue 4, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1003431