Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts

Mol Cell Biol. 2011 Sep;31(17):3630-8. doi: 10.1128/MCB.01462-10. Epub 2011 Jul 5.


Trichothiodystrophy (TTD) is a rare autosomal premature-ageing and neuroectodermal disease. The photohypersensitive form of TTD is caused by inherited mutations in three of the 10 subunits of the basal transcription factor TFIIH. TFIIH is an essential transcription initiation factor that is also pivotal for nucleotide excision repair (NER). Photosensitive TTD is explained by deficient NER, dedicated to removing UV-induced DNA lesions. TTD group A (TTD-A) patients carry mutations in the smallest TFIIH subunit, TTDA, which is an 8-kDa protein that dynamically interacts with TFIIH. TTD-A patients display a relatively mild TTD phenotype, and TTD-A primary fibroblasts exhibit moderate UV sensitivity despite a rather low level of UV-induced unscheduled DNA synthesis (UDS). To investigate the rationale of this seeming discrepancy, we studied the repair kinetics and the binding kinetics of TFIIH downstream NER factors to damaged sites in TTD-A cells. Our results show that TTD-A cells do repair UV lesions, although with reduced efficiency, and that the binding of downstream NER factors on damaged DNA is not completely abolished but only retarded. We conclude that in TTD-A cells repair is not fully compromised but only delayed, and we present a model that explains the relatively mild photosensitive phenotype observed in TTD-A patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line
  • Cell Survival / genetics
  • Cell Survival / radiation effects
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • DNA / genetics
  • DNA / metabolism
  • DNA Damage*
  • DNA Repair / genetics*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endonucleases / genetics
  • Endonucleases / metabolism
  • Fibroblasts / metabolism*
  • Fibroblasts / radiation effects
  • Humans
  • Pyrimidine Dimers / metabolism
  • Time Factors
  • Transcription Factor TFIIH / genetics
  • Transcription Factor TFIIH / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Trichothiodystrophy Syndromes / genetics*
  • Trichothiodystrophy Syndromes / metabolism
  • Trichothiodystrophy Syndromes / pathology
  • Ultraviolet Rays
  • Xeroderma Pigmentosum / genetics
  • Xeroderma Pigmentosum / metabolism
  • Xeroderma Pigmentosum / pathology
  • Xeroderma Pigmentosum Group A Protein / genetics
  • Xeroderma Pigmentosum Group A Protein / metabolism


  • DNA-Binding Proteins
  • GTF2H5 protein, human
  • Pyrimidine Dimers
  • Transcription Factors
  • XPA protein, human
  • Xeroderma Pigmentosum Group A Protein
  • pyrimidine-pyrimidone dimer
  • Transcription Factor TFIIH
  • DNA
  • ERCC1 protein, human
  • Endonucleases