title: Generation of DNA single-strand displacement by compromised nucleotide excision repair.
abstract: Nucleotide excision repair (NER) is a precisely coordinated process essential to avoid DNA damage-induced cellular malfunction and mutagenesis. Here, we investigate the mechanistic details and effects of the NER machinery when it is compromised by a pathologically significant mutation in a subunit of the repair/transcription factor TFIIH, namely XPD. In contrast to previous studies, we find that no single- or double-strand DNA breaks are produced at early time points after UV irradiation of cells bearing a specific XPD mutation, despite the presence of a clear histone H2AX phosphorylation (γH2AX) signal in the UV-exposed areas. We show that the observed γH2AX signal can be explained by the presence of longer single-strand gaps possibly generated by strand displacement. Our in vivo measurements also indicate a strongly reduced TFIIH-XPG binding that could promote single-strand displacement at the site of UV lesions. This finding not only highlights the crucial role of XPG's interactions with TFIIH for proper NER, but also sheds new light on how a faulty DNA repair process can induce extreme genomic instability in human patients.
authors.affiliation: Department of Cancer Biology, CNRS, IPBS, Toulouse, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Godon
authors.forename: Sophie
authors.initials: S
authors.lastname: Mourgues
authors.forename: Julie
authors.initials: J
authors.lastname: Nonnekens
authors.forename: Amandine
authors.initials: A
authors.lastname: Mourcet
authors.forename: Fréderic
authors.initials: F
authors.lastname: Coin
authors.forename: Wim
authors.initials: W
authors.lastname: Vermeulen
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Mari
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Giglia-Mari
mesh_terms: D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004277:DNA, Single-Stranded / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014466:Ultraviolet Rays; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D014157:Transcription Factors; D051759:Xeroderma Pigmentosum Group D Protein; D000099250:DNA Excision Repair Protein ERCC-5; C497293:Ercc2 protein, mouse