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Title: Investigation into the importance of DNA repair gene Ercc1 in the skin and central nervous system
Author: Lawrence, Nicola
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Nucleotide excision repair (NER) is responsible for the removal of helix distorting lesions from DNA. In NER, ERCC1 acts in complex with XPF to make an incision 5’ of the lesion and as such is essential for this damage repair process. Ercc1 null mice die at 3 weeks with severe liver abnormalities, so in the laboratory we have created two longer lived Ercc1 deficient models: firstly a liver corrected Ercc1 null, and secondly an epidermis specific Ercc1 knockout. In this study I considered the short and long term effects of UV irradiation on the skin using the epidermis specific Ercc1 knockout, in particular the consequences of unrepaired DNA damage in keratinocytes on UV induced erythema, immunosuppression, tanning and carcinogenesis. I found the epidermis specific Ercc1 knockout mice to be extremely sensitive in all these respects. As these mice have NER deficient keratinocytes but NER proficient fibroblasts, immunological cells and melanocytes, I was able to show that DNA damage in keratinocytes is responsible for initiating a cascade of events that leads to systemic immunosuppression, and I also report that DNA damage in keratinocytes alone leads to UV induced tanning. I went on to use these mice to investigate a proposed anti-cancer therapy, the topical application of thymidine dinucleotides. I have also further characterised the liver corrected Ercc1null mouse, specifically the neurological features and an unusual hair phenotype that was observed. I report that progressive ataxia in animals with an Ercc1 deficient nervous system is due to chronic uraemia caused by kidney pathology. Furthermore, I characterised a brittle hair phenotype in these mice, and concluded that it was due to an unidentified background effect rather than a specific trait caused by lack of Ercc1.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available