The role of CSA in the response to oxidative DNA damage in human cells
Cockayne syndrome (CS) is a rare genetic disease characterized by severe growth, mental retardation and pronounced cachexia. CS is most frequently due to mutations in either of two genes, CSB and CSA . Evidence for a role of CSB protein in the repair of oxidative DNA damage has been provided recentl...
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Veröffentlicht in: | Oncogene 2007-06, Vol.26 (30), p.4336-4343 |
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Sprache: | eng |
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Zusammenfassung: | Cockayne syndrome (CS) is a rare genetic disease characterized by severe growth, mental retardation and pronounced cachexia. CS is most frequently due to mutations in either of two genes,
CSB
and
CSA
. Evidence for a role of CSB protein in the repair of oxidative DNA damage has been provided recently. Here, we show that CSA is also involved in the response to oxidative stress. CS-A human primary fibroblasts and keratinocytes showed hypersensitivity to potassium bromate, a specific inducer of oxidative damage. This was associated with inefficient repair of oxidatively induced DNA lesions, namely 8-hydroxyguanine (8-OH-Gua) and (5′S)-8,5′-cyclo 2′-deoxyadenosine. Expression of the wild-type CSA in the CS-A cell line CS3BE significantly decreased the steady-state level of 8-OH-Gua and increased its repair rate following oxidant treatment. CS-A cell extracts showed normal 8-OH-Gua cleavage activity in an
in vitro
assay, whereas CS-B cell extracts were confirmed to be defective. Our data provide the first
in vivo
evidence that CSA protein contributes to prevent accumulation of various oxidized DNA bases and underline specific functions of CSB not shared with CSA. These findings support the hypothesis that defective repair of oxidative DNA damage is involved in the clinical features of CS patients. |
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ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/sj.onc.1210232 |