DNA Repair 1 (2002) 143–157 UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice Gijsbertus T.J. van der Horst a , Lisiane Meira b , Theo G.M.F. Gorgels a , Jan de Wit a , Susana Velasco-Miguel b , James A. Richardson b , Yvonne Kamp a , Maaike P.G. Vreeswijk c , Bep Smit a , Dirk Bootsma a , Jan H.J. Hoeijmakers a,∗ , Errol C. Friedberg b a Department of Cell Biology and Genetics, Medical Genetics Centre, Erasmus University Rotterdam, Box 1738, 3000 Rotterdam DR, The Netherlands b Department of Pathology, Laboratory of Molecular Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA c MGC Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, Leiden, The Netherlands Accepted 6 November 2001 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. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Cockayne syndrome; UV-radiation; Nucleotide excision repair 1. Introduction The chemical integrity of the genome is continu- ously threatened by a variety of environmental and endogenous agents that damage the DNA and interfere ∗ Corresponding author. Tel.: +31-1-408-7199; fax: +31-1-408-9468. E-mail address: hoeijmakers@gen.fgg.eur.nl (J.H.J. Hoeijmakers). with vital DNA-metabolizing processes, most notably DNA transcription and replication. Immediate effects of DNA damage include a physical block to tran- scription, which can cause cell death via apoptosis. Long-term effects of DNA damage involve induction of mutations via replication of damaged DNA, which can ultimately lead to the neoplastic transformation of cells [1]. To withstand the potentially lethal and mutagenic effects of DNA damage, all living cells are 1568-7864/02/$ – see front matter © 2002 Elsevier Science B.V. All rights reserved. PII:S1568-7864(01)00010-6