title: DNA repair and transcriptional deficiencies caused by mutations in the Drosophila p52 subunit of TFIIH generate developmental defects and chromosome fragility.
abstract: The transcription and DNA repair factor TFIIH is composed of 10 subunits. Mutations in the XPB, XPD, and p8 subunits are genetically linked to human diseases, including cancer. However, no reports of mutations in other TFIIH subunits have been reported in higher eukaryotes. Here, we analyze at genetic, molecular, and biochemical levels the Drosophila melanogaster p52 (DMP52) subunit of TFIIH. We found that DMP52 is encoded by the gene marionette in Drosophila and that a defective DMP52 produces UV light-sensitive flies and specific phenotypes during development: organisms are smaller than their wild-type siblings and present tumors and chromosomal instability. The human homologue of DMP52 partially rescues some of these phenotypes. Some of the defects observed in the fly caused by mutations in DMP52 generate trichothiodystrophy and cancer-like phenotypes. Biochemical analysis of DMP52 point mutations introduced in human p52 at positions homologous to those of defects in DMP52 destabilize the interaction between p52 and XPB, another TFIIH subunit, thus compromising the assembly of the complex. This study significantly extends the role of p52 in regulating XPB ATPase activity and, consequently, both its transcriptional and nucleotide excision repair functions.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404 Illkirch Cedex, C.U. de Strasbourg, France.
authors.forename: Mariana
authors.initials: M
authors.lastname: Fregoso
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lainé
authors.forename: Javier
authors.initials: J
authors.lastname: Aguilar-Fuentes
authors.forename: Vincent
authors.initials: V
authors.lastname: Mocquet
authors.forename: Enrique
authors.initials: E
authors.lastname: Reynaud
authors.forename: Frédéric
authors.initials: F
authors.lastname: Coin
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: Mario
authors.initials: M
authors.lastname: Zurita
mesh_terms: D000818:Animals; D043171:Chromosomal Instability; D002873:Chromosome Fragility; D004260:DNA Repair; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000235:genetics* / Q000254:growth & development*; D005816:Genetic Complementation Test; D007814:Larva / Q000033:anatomy & histology / Q000502:physiology / Q000528:radiation effects; D010641:Phenotype; D017354:Point Mutation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D051758:Transcription Factor TFIIH / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
chemical_list: D029721:Drosophila Proteins; D021122:Protein Subunits; C520555:mrn protein, Drosophila; D051758:Transcription Factor TFIIH