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Long-term XPC Silencing Reduces DNA Double-Strand Break Repair

¹ Commissariat à l'Energie Atomique, Laboratoire de Génétique de la Radiosensibilité, Département de Radiobiologie et de Radiopathologie, Direction des Sciences du Vivant, Fontenay-aux-Roses, France; ² Institute for Genetics, Department of Biology and Geography of the University of Duisburg-Essen, Essen, Germany; and ³ Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, UMR 5089, Toulouse Cedex 4, France

Requests for reprints: Emmanuelle Despras, CEA-DSV-DRR, Laboratoire de Génétique de la Radiosensibilité, BP 6, 92265 Fontenay aux Roses, France. Phone: 33-1-46-54-87-47; Fax: 33-1-46-54-87-34; E-mail: emmanuelle.despras{at}cea.fr.

To study the relationships between different DNA repair pathways, we established a set of clones in which one specific DNA repair gene was silenced using long-term RNA interference in HeLa cell line. We focus here on genes involved in either nucleotide excision repair (XPA and XPC) or nonhomologous end joining (NHEJ; DNA-PKcs and XRCC4). As expected, XPA^KD (knock down) and XPC^KD cells were highly sensitive to UVC. DNA-PKcs^KD and XRCC4^KD cells presented an increased sensitivity to various inducers of double-strand breaks (DSBs) and a 70% to 80% reduction of in vitro NHEJ activity. Long-term silencing of XPC gene expression led to an increased sensitivity to etoposide, a topoisomerase II inhibitor that creates DSBs through the progression of DNA replication forks. XPC^KD cells also showed intolerance toward acute -ray irradiation. We showed that XPC^KD cells exhibited an altered spectrum of NHEJ products with decreased levels of intramolecular joined products. Moreover, in both XPC^KD and DNA-PKcs^KD cells, XRCC4 and ligase IV proteins were mobilized on damaged nuclear structures at lower doses of DSB inducer. In XPC-proficient cells, XPC protein was released from nuclear structures after induction of DSBs. By contrast, silencing of XPA gene expression did not have any effect on sensitivity to DSB or NHEJ. Our results suggest that XPC deficiency, certainly in combination with other genetic defects, may contribute to impair DSB repair. [Cancer Res 2007;67(6):2526–34]

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