title: The role of CSA in the response to oxidative DNA damage in human cells.
abstract: 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.
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Errico
authors.forename: E
authors.initials: E
authors.lastname: Parlanti
authors.forename: M
authors.initials: M
authors.lastname: Teson
authors.forename: P
authors.initials: P
authors.lastname: Degan
authors.forename: T
authors.initials: T
authors.lastname: Lemma
authors.forename: A
authors.initials: A
authors.lastname: Calcagnile
authors.forename: I
authors.initials: I
authors.lastname: Iavarone
authors.forename: P
authors.initials: P
authors.lastname: Jaruga
authors.forename: M
authors.initials: M
authors.lastname: Ropolo
authors.forename: A M
authors.initials: AM
authors.lastname: Pedrini
authors.forename: D
authors.initials: D
authors.lastname: Orioli
authors.forename: G
authors.initials: G
authors.lastname: Frosina
authors.forename: G
authors.initials: G
authors.lastname: Zambruno
authors.forename: M
authors.initials: M
authors.lastname: Dizdaroglu
authors.forename: M
authors.initials: M
authors.lastname: Stefanini
authors.forename: E
authors.initials: E
authors.lastname: Dogliotti
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D004249:DNA Damage; D004265:DNA Helicases / Q000502:physiology; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000502:physiology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D010084:Oxidation-Reduction; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C095472:ERCC8 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes; D003849:Deoxyguanosine