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

Karen L. Thijssen, Melanie van der Woude, Carlota Davó-Martínez, Dick H.W. Dekkers, Mariangela Sabatella, Jeroen A.A. Demmers, Wim Vermeulen, Hannes Lans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Article number1336
JournalCommunications Biology
Volume4
Issue number1
DOIs
Publication statusPublished - 25 Nov 2021

Bibliographical note

Funding Information:
We thank Dr. A. Theil for advice, Dr. G. Jansen for use of his injection microscope, Dr. Heng-Chi Lee and Dr. Andrew Fire for strains and plasmids and Dr. G. van Cappellen and the Erasmus MC Optical Imaging Center for microscope support. Some strains were provided by the Caenorhabditis Genetics Center (funded by NIH Office of Research Infrastructure Programs P40 OD010440) and the National Bioresource Project for the nematode. This work was supported by the Netherlands Organization for Scientific Research (711.018.007 and ALWOP.494), the Marie Curie Initial Training Network “aDDRess” funded by the European Commission 7th Framework Programme (316390), the European Research Council (advanced grant 340988-ERC-ID), and the gravitation program Cancer-GenomiCs.nl from the Netherlands Organization for Scientific Research. Oncode Institute is partly financed by the Dutch Cancer Society.

Publisher Copyright:
© 2021, The Author(s).

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