UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice.
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.
|Keywords||0 (CKN1 protein, human), 0 (Proteins), 63231-63-0 (rna), Amino Acid Sequence, Animals, Cockayne Syndrome/etiology/*genetics/pathology, DNA Damage, DNA Repair/*physiology/radiation effects, Disease Models, Animal, Female, Fibroblasts/radiation effects, Genetic Complementation Test, Genetic Predisposition to Disease, Human, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Neoplasms, Radiation-Induced/etiology/*genetics/pathology, Proteins/*genetics/metabolism, RNA/genetics/metabolism, Sequence Homology, Amino Acid, Skin Neoplasms/etiology, Skin/radiation effects, Support, Non-U.S. Gov't, Support, U.S. Gov't, P.H.S., Ultraviolet Rays|
|Persistent URL||dx.doi.org/10.1016/S1568-7864(01)00010-6, hdl.handle.net/1765/3204|
Meira, L., Gorgels, T.G.M.F., de Wit, J., Velasco-Miguel, S., Richardson, J.A., Kamp, Y., … van der Horst, G.T.J.. (2002). UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice.. D N A Repair, 1(2), 143–157. doi:10.1016/S1568-7864(01)00010-6