title: Different effects of CSA and CSB deficiency on sensitivity to oxidative DNA damage.
abstract: Mutations in the CSA and CSB genes cause Cockayne syndrome, a rare inherited disorder characterized by UV sensitivity, severe neurological abnormalities, and progeriod symptoms. Both gene products function in the transcription-coupled repair (TCR) subpathway of nucleotide excision repair (NER), providing the cell with a mechanism to remove transcription-blocking lesions from the transcribed strands of actively transcribed genes. Besides a function in TCR of NER lesions, a role of CSB in (transcription-coupled) repair of oxidative DNA damage has been suggested. In this study we used mouse models to compare the effect of a CSA or a CSB defect on oxidative DNA damage sensitivity at the levels of the cell and the intact organism. In contrast to CSB(-/-) mouse embryonic fibroblasts (MEFs), CSA(-/-) MEFs are not hypersensitive to gamma-ray or paraquat treatment. Similar results were obtained for keratinocytes. In contrast, both CSB(-/-) and CSA(-/-) embryonic stem cells show slight gamma-ray sensitivity. Finally, CSB(-/-) but not CSA(-/-) mice fed with food containing di(2-ethylhexyl)phthalate (causing elevated levels of oxidative DNA damage in the liver) show weight reduction. These findings not only uncover a clear difference in oxidative DNA damage sensitivity between CSA- and CSB-deficient cell lines and mice but also show that sensitivity to oxidative DNA damage is not a uniform characteristic of Cockayne syndrome. This difference in the DNA damage response between CSA- and CSB-deficient cells is unexpected, since until now no consistent differences between CSA and CSB patients have been reported. We suggest that the CSA and CSB proteins in part perform separate roles in different DNA damage response pathways.
authors.affiliation: MGC, Department of Cell Biology and Genetics, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: Harm
authors.initials: H
authors.lastname: de Waard
authors.forename: Jan
authors.initials: J
authors.lastname: de Wit
authors.forename: Jaan-Olle
authors.initials: JO
authors.lastname: Andressoo
authors.forename: Conny T M
authors.initials: CT
authors.lastname: van Oostrom
authors.forename: Bente
authors.initials: B
authors.lastname: Riis
authors.forename: Allan
authors.initials: A
authors.lastname: Weimann
authors.forename: Henrik E
authors.initials: HE
authors.lastname: Poulsen
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
mesh_terms: D000818:Animals; D002460:Cell Line; D003057:Cockayne Syndrome / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000172:deficiency* / Q000235:genetics; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D004351:Drug Resistance / Q000235:genetics; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity; D000075223:Poly-ADP-Ribose Binding Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000235:genetics; D014157:Transcription Factors; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: C490652:Ckn1 protein, mouse; D004268:DNA-Binding Proteins; C095472:ERCC8 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D004051:Diethylhexyl Phthalate; D004265:DNA Helicases; C078673:ERCC6 protein, human; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes; D010269:Paraquat