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Title: The role of DNA repair gene Ercc1 in the liver
Author: Kirschner, Kristina
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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AdenoCre infection of hepatocyte cultures led to high levels of recombination with no ERCC1 protein remaining at 48 hours after infection. Flow cytometry failed to show high levels of polyploidy in knockout hepatocytes 1 week after infection. This differed from the premature polyploidy seen in this study in Ercc1-deficient livers. We used AdenoCre to reduce ERCC1 levels in adult liver in vivo. Low levels of recombination resulted in increased Ploidy, indicating that polyploidisation may be a protective mechanism triggered by increased levels of DNA damage in Ercc1-deficient liver. Ercc1-deficient hepatocytes in vitro underwent higher levels of spontaneous UV- and oxidative damage- induced apoptosis than control cultures, implying that Ercc1 is essential for liver maintenance. Lipid accumulation was observed in older Ercc1-deficient hepatocyte cultures, one week after AdenoCre infection in vivo and also in young Erc1-deficient and wild type livers. Lipids disappeared in the wild type controls with age, but persisted in Ercc1 null livers. These findings suggest that a reduced ability to repair oxidative DNA damage and a malfunction of oxidative pathways could be responsible for the Ercc1-deficient liver phenotype. Regeneration of liver following exposure to carbon tetrachloride in AdenoCre infected livers led to an increase in Ploidy and S-phase independent of genotype, masking the increased Ploidy resulting from AdenoCre induced Ercc1 deficiency. Livers from simple Ercc1 knockout mice shoed no increase in malondialdehyde adducts. However, higher levels of reactive oxygen species were detected in young Ercc1-deficient livers compared to controls. Real time RT-PCR was used to determine differences in expression of cell cycle regulation and survival genes between Ercc1-deficient and control livers.  We succeeded in characterising Ercc1 deficiency in the liver further.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available