title: Correction by the ERCC2 gene of UV sensitivity and repair deficiency phenotype in a subset of trichothiodystrophy cells.
abstract: Trichothiodystrophy (TTD) is a rare genetic disease with heterogeneous clinical features associated with specific deficiencies in nucleotide excision repair. Patients have brittle hair due to a reduced content of cysteine-rich matrix proteins. About 50% of the cases reported in the literature are photosensitive. In these patients an altered cellular response to UV, due to a specific deficiency in nucleotide excision repair, has been observed. The majority of repair-defective TTD patients have been assigned by complementation analysis to group D of xeroderma pigmentosum (XP). Recently, the human excision repair gene ERCC2 has been shown to correct the UV sensitivity of XP-D fibroblasts. In this work we describe the effect of ERCC2 on the DNA repair deficient phenotype of XP-D and on two repair-defective TTD cell strains (TTD1VI and TTD2VI) assigned by complementation analysis to group D of XP. ERCC2 cDNA, cloned into a mammalian expression vector, was introduced into TTD and XP fibroblasts via DNA-mediated transfection or microneedle injection. UV sensitivity and cellular DNA repair properties, including unscheduled DNA synthesis and reactivation of a UV-irradiated plasmid containing the chloramphenicol acetyltransferase reporter gene (pRSVCat), were corrected to wild-type levels in both TTD and XP-D cells. These data show that a functional ERCC2 gene is sufficient to reestablish a wild-type DNA repair phenotype in TTD1VI and TTD2VI cells, confirming the genetic relationship between TTD and XP-D. Furthermore, our findings suggest that mutations at the ERCC2 locus are responsible for causing a similar phenotype in TTD and XP-D cells in response to UV irradiation, but produce quite different clinical symptoms.
authors.affiliation: Laboratory of Molecular Genetics, UPR42 CNRS IFC H01, Villejuif, France.
authors.forename: M
authors.initials: M
authors.lastname: Mezzina
authors.forename: E
authors.initials: E
authors.lastname: Eveno
authors.forename: O
authors.initials: O
authors.lastname: Chevallier-Lagente
authors.forename: A
authors.initials: A
authors.lastname: Benoit
authors.forename: M
authors.initials: M
authors.lastname: Carreau
authors.forename: W
authors.initials: W
authors.lastname: Vermeulen
authors.forename: J H
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: M
authors.initials: M
authors.lastname: Stefanini
authors.forename: A R
authors.initials: AR
authors.lastname: Lehmann
authors.forename: C A
authors.initials: CA
authors.lastname: Weber
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D006224:Cricetinae; D004265:DNA Helicases; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005260:Female; D006201:Hair Diseases / Q000235:genetics*; D006801:Humans; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D011836:Radiation Tolerance; D014157:Transcription Factors; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human