title: UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice.
abstract: Cockayne syndrome (CS) is an inherited photosensitive neurodevelopmental disorder caused by a specific defect in the transcription-coupled repair (TCR) sub-pathway of NER. Remarkably, despite their DNA repair deficiency, CS patients do not develop skin cancer. Here, we present a mouse model for CS complementation group A. Like cells from CS-A patients, Csa-/- mouse embryonic fibroblasts (MEFs): (i) are ultraviolet (UV)-sensitive; (ii) show normal unscheduled DNA synthesis (indicating that the global genome repair sub-pathway is unaffected); (iii) fail to resume RNA synthesis after UV-exposure and (iv) are unable to remove cyclobutane pyrimidine dimers (CPD) photolesions from the transcribed strand of active genes. CS-A mice exhibit UV-sensitivity and pronounced age-dependent loss of retinal photoreceptor cells but otherwise fail to show the severe developmental and neurological abnormalities of the human syndrome. In contrast to human CS, Csa-/- animals develop skin tumors after chronic exposure to UV light, indicating that TCR in mice protects from UV-induced skin cancer development. Strikingly, inactivation of one Xpc allele (encoding a component of the damage recognition complex involved in the global genome repair sub-pathway) in Csa-/- mice resulted in a strongly enhanced UV-mediated skin cancer sensitivity, indicating that in a TC repair defective background, the Xpc gene product may be a rate-limiting factor in the removal of UV-induced DNA lesions.
authors.affiliation: Department of Cell Biology and Genetics, Medical Genetics Centre, Erasmus University Rotterdam, The Netherlands.
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: Lisiane
authors.initials: L
authors.lastname: Meira
authors.forename: Theo G M F
authors.initials: TG
authors.lastname: Gorgels
authors.forename: Jan
authors.initials: J
authors.lastname: de Wit
authors.forename: Susana
authors.initials: S
authors.lastname: Velasco-Miguel
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kamp
authors.forename: Maaike P G
authors.initials: MP
authors.lastname: Vreeswijk
authors.forename: Bep
authors.initials: B
authors.lastname: Smit
authors.forename: Dirk
authors.initials: D
authors.lastname: Bootsma
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Errol C
authors.initials: EC
authors.lastname: Friedberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003057:Cockayne Syndrome / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology* / Q000528:radiation effects; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000528:radiation effects; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology; D014157:Transcription Factors; D014466:Ultraviolet Rays
chemical_list: C490652:Ckn1 protein, mouse; D004268:DNA-Binding Proteins; C095472:ERCC8 protein, human; D011506:Proteins; D014157:Transcription Factors; D012313:RNA; D045643:DNA Repair Enzymes