C. elegans TFIIH subunit GTF-2H5/TTDA is a non-essential transcription factor indispensable for DNA repair

The 10-subunit TFIIH complex is vital to transcription and nucleotide excision repair. Hereditary mutations in its smallest subunit, TTDA/GTF2H5, cause a photosensitive form of the rare developmental disorder trichothiodystrophy. Some trichothiodystrophy features are thought to be caused by subtle transcription or gene expression defects. TTDA/GTF2H5 knockout mice are not viable, making it difficult to investigate TTDA/GTF2H5 in vivo function. Here we show that deficiency of C. elegans TTDA ortholog GTF-2H5 is, however, compatible with life, in contrast to depletion of other TFIIH subunits. GTF-2H5 promotes TFIIH stability in multiple tissues and is indispensable for nucleotide excision repair, in which it facilitates recruitment of TFIIH to DNA damage. Strikingly, when transcription is challenged, gtf-2H5 embryos die due to the intrinsic TFIIH fragility in absence of GTF-2H5. These results support the idea that TTDA/GTF2H5 mutations cause transcription impairment underlying trichothiodystrophy and establish C. elegans as model for studying pathogenesis of this disease. Hereditary mutations in TTDA/GTF2H5 cause a photosensitive form of the rare developmental disorder trichothiodystrophy, however the development of models has been hampered by mutations being lethal. Thijssen et al. show that deficiency of C. elegans TTDA ortholog GTF-2H5 is, compatible with life, in contrast to depletion of other TFIIH subunits and thus propose that this model could be used for studying the pathogenesis of trichothiodystrophy.

Automated summary

The TFIIH complex is essential for transcription and nucleotide excision repair, with mutations in its smallest subunit TTDA/GTF2H5 leading to trichothiodystrophy. While TTDA/GTF2H5 knockout mice are not viable, a C. elegans model shows GTF-2H5 deficiency is compatible with life and can be used for studying the disease's pathogenesis.