Different effects of CSA and CSB deficiency on sensitivity to oxidative DNA damage

Harm De Waard, Jan De Wit, Jaan Olle Andressoo, Conny T.M. Van Oostrom, Bente Riis, Allan Weimann, Henrik E. Poulsen, Harry Van Steeg, Jan H.J. Hoeijmakers, Gijsbertus T.J. Van Der Horst

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

88 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)7941-7948
Aantal pagina's8
TijdschriftMolecular and Cellular Biology
Volume24
Nummer van het tijdschrift18
DOI's
StatusGepubliceerd - sep. 2004
Extern gepubliceerdJa

Vingerafdruk

Duik in de onderzoeksthema's van 'Different effects of CSA and CSB deficiency on sensitivity to oxidative DNA damage'. Samen vormen ze een unieke vingerafdruk.

Citeer dit