Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality.
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 show...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-04-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3630102?pdf=render |
| _version_ | 1818109649784668160 |
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| author | Arjan F Theil Julie Nonnekens Barbara Steurer Pierre-Olivier Mari Jan de Wit Charlène Lemaitre Jurgen A Marteijn Anja Raams Alex Maas Marcel Vermeij Jeroen Essers Jan H J Hoeijmakers Giuseppina Giglia-Mari Wim Vermeulen |
| author_facet | Arjan F Theil Julie Nonnekens Barbara Steurer Pierre-Olivier Mari Jan de Wit Charlène Lemaitre Jurgen A Marteijn Anja Raams Alex Maas Marcel Vermeij Jeroen Essers Jan H J Hoeijmakers Giuseppina Giglia-Mari Wim Vermeulen |
| author_sort | Arjan F Theil |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T02:34:37Z |
| format | Article |
| id | doaj.art-7d60226eb215453780f9c39c8c311231 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-11T02:34:37Z |
| publishDate | 2013-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-7d60226eb215453780f9c39c8c3112312022-12-22T01:23:46ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-04-0194e100343110.1371/journal.pgen.1003431Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality.Arjan F TheilJulie NonnekensBarbara SteurerPierre-Olivier MariJan de WitCharlène LemaitreJurgen A MarteijnAnja RaamsAlex MaasMarcel VermeijJeroen EssersJan H J HoeijmakersGiuseppina Giglia-MariWim VermeulenThe 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.http://europepmc.org/articles/PMC3630102?pdf=render |
| spellingShingle | Arjan F Theil Julie Nonnekens Barbara Steurer Pierre-Olivier Mari Jan de Wit Charlène Lemaitre Jurgen A Marteijn Anja Raams Alex Maas Marcel Vermeij Jeroen Essers Jan H J Hoeijmakers Giuseppina Giglia-Mari Wim Vermeulen Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality. PLoS Genetics |
| title | Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality. |
| title_full | Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality. |
| title_fullStr | Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality. |
| title_full_unstemmed | Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality. |
| title_short | Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality. |
| title_sort | disruption of ttda results in complete nucleotide excision repair deficiency and embryonic lethality |
| url | http://europepmc.org/articles/PMC3630102?pdf=render |
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