title: Mutations in TFIIH causing trichothiodystrophy are responsible for defects in ribosomal RNA production and processing.
abstract: The basal transcription/repair factor II H (TFIIH), found mutated in cancer-prone or premature aging diseases, plays a still unclear role in RNA polymerase I transcription. Furthermore, the impact of this function on TFIIH-related diseases, such as trichothiodystrophy (TTD), remains to be explored. Here, we studied the involvement of TFIIH during the whole process of ribosome biogenesis, from RNAP1 transcription to maturation steps of the ribosomal RNAs. Our results show that TFIIH is recruited to the ribosomal DNA in an active transcription-dependent manner and functions in RNAP1 transcription elongation through ATP hydrolysis of the XPB subunit. Remarkably, we found a TFIIH allele-specific effect, affecting RNAP1 transcription and/or the pre-rRNA maturation process. Interestingly, this effect was observed in mutant TFIIH-TTD cells and also in the brains of TFIIH-TTD mice. Our findings provide evidence that defective ribosome synthesis represents a new faulty mechanism involved in the pathophysiology of TFIIH-related diseases.
authors.affiliation: Centre national de la recherche scientifique CNRS, Institute of Pharmacology and Structural Biology IPBS, 205 route de Narbonne, Toulouse F-31077, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Nonnekens
authors.forename: Jorge
authors.initials: J
authors.lastname: Perez-Fernandez
authors.forename: Arjan F
authors.initials: AF
authors.lastname: Theil
authors.forename: Olivier
authors.initials: O
authors.lastname: Gadal
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Bonnart
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Giglia-Mari
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D012318:RNA Polymerase I / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012335:RNA, Ribosomal / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D054463:Trichothiodystrophy Syndromes / Q000235:genetics* / Q000378:metabolism
chemical_list: D012335:RNA, Ribosomal; D051758:Transcription Factor TFIIH; D012318:RNA Polymerase I