UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice

Gijsbertus T J Van Der Horst, Lisiane Meira, Theo G M F Gorgels, Jan De Wit, Susana Velasco-Miguel, James A. Richardson, Yvonne Kamp, Maaike P G Vreeswijk, Bep Smit, Dirk Bootsma, Jan H J Hoeijmakers, Errol C. Friedberg

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)143-157
Number of pages15
JournalDNA repair
Issue number2
StatePublished - 2002


  • Cockayne syndrome
  • Nucleotide excision repair
  • UV-radiation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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