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Mol. Cell. Biol. doi:10.1128/MCB.00030-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

DNA repair and transcriptional deficiencies caused by mutations in the Drosophila p52 subunit of TFIIH generate developmental defects and chromosome fragility

Department of Developmental Genetics, Instituto de Biotecnología, Universidad Nacional, Autónoma de México. Av. Universidad 2001, Cuernavaca Morelos 62250, México.; Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404 Illkirch Cedex, C.U. de Strasbourg, France

^* To whom correspondence should be addressed. Email: egly{at}titus.u-strasbg.fr. marioz{at}ibt.unam.mx.

	Abstract

The transcription and DNA repair factor TFIIH is composed by ten 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 at biochemical levels the Drosophila 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, presenting 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 (TTD) and cancer like phenotypes. Biochemical analysis of Dmp52 point mutations introduced in human p52, at homologous positions to 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 the XPB ATPase activity and consequently both of its transcriptional and NER functions.

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