Abstract
Ercc1 has an essential role in the nucleotide excision repair (NER) pathway that protects against ultraviolet (UV)-induced DNA damage and is also involved in additional repair pathways. The premature death of simple Ercc1 mouse knockouts meant that we were unable to study the role of Ercc1 in the skin. To do this, we have used the Cre–lox system to generate a skin-specific Ercc1 knockout. With a Cre transgene under control of the bovine keratin 5 promoter we achieved 100% recombination of the Ercc1 gene in the epidermis. Hairless mice with Ercc1-deficient skin were hypersensitive to the short-term effects of UV irradiation, showing a very low minimal erythemal dose and a dramatic hyperproliferative response. Ultraviolet-irradiated mice with Ercc1-deficient skin developed epidermal skin tumours much more rapidly than controls. These tumours appeared to arise earlier in actinic progression and grew more rapidly than tumours on control mice. These responses are more pronounced than have been reported for other NER-deficient mice, demonstrating that Ercc1 has a key role in protecting against UV-induced skin cancer.
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Acknowledgements
Ultraviolet dosimetry was carried out by Dr Stephen Pye (Lothian University Hospitals NHS Trust). The Ercc1 gene targeting was carried out by Kan-Tai Hsia. Ercc1 skin-specific knockout mice were produced with the support of a programme Grant (SP2095/0301) from Cancer Research UK to DWM. The UV irradiation work on these mice was supported by a project grant from the Association for International Cancer Research to DWM. NJL was supported by a PhD scholarship from the Raven Trust.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Doig, J., Anderson, C., Lawrence, N. et al. Mice with skin-specific DNA repair gene (Ercc1) inactivation are hypersensitive to ultraviolet irradiation-induced skin cancer and show more rapid actinic progression. Oncogene 25, 6229–6238 (2006). https://doi.org/10.1038/sj.onc.1209642
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DOI: https://doi.org/10.1038/sj.onc.1209642
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