Transcription-coupled repair: impact on UV-induced mutagenesis in cultured rodent cells and mouse skin tumors.
UV-induced cyclobutane pyrimidine dimers (CPDs) are removed with accelerated speed from the transcribed strand of expressed genes in cultured mammalian cells by a process called transcription-coupled repair (TCR). It has been previously shown that this phenomenon has consequences for the molecular nature of the mutations induced by UV-light. Here, we review these data and show that TCR has not only a clear impact on UV-induced mutations in cultured mammalian cells but also on genes involved in tumor formation in the skin of UV-exposed mice. Mutations observed in the p53 gene in UV-induced squamous cell carcinoma are predominantly found at sites of dipyrimidines in the non-transcribed strand. In contrast, in UVC-irradiated Csb(-/-) Chinese hamster cells and in UVB-induced tumors in the Csb(-/-) mouse, almost all mutations are at positions of dipyrimidine sites in the transcribed strand of the mutated gene. Csb(-/-) mice appear to be susceptible to UVB-induced skin cancer in contrast to the human CSB patients. We speculate that the UVB-induced cancer susceptibility of Csb(-/-) mice is related to the absence of TCR as well as to a lack of a compensating global genome repair system for CPDs in mice.
van Zeeland
Albert A
AA
Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.
Vreeswijk
Maaike P G
MP
de Gruijl
Frank R
FR
van Kranen
Henk J
HJ
Vrieling
Harry
H
Mullenders
Leon F H
LF
D000818:Animals; D002478:Cells, Cultured; D004260:DNA Repair; D051379:Mice; D016296:Mutagenesis; D012878:Skin Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic; D014466:Ultraviolet Rays