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Title: Analysis of germline mutation rates in DNA-repair deficient mice
Author: Burr, Karen Lesley-Anne
ISNI:       0000 0001 3511 118X
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2005
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Expanded simple tandem repeat (ESTR) loci provide a useful and sensitive tool for the analysis of germline mutation induction in male mice; however the mechanisms that act at ESTR loci causing instability remain unknown. Understanding of mutational processes at ESTR loci may provide important information about the damaging effects of exposure to mutagens at the genome level. To investigate the possibility that mutations at ESTR loci may be a by-product of DNA damage responses mice with mutations at genes involved in DNA repair/apoptosis have been analysed. Through this analysis it was hoped to determine whether DNA repair/apoptosis were involved in the mechanism of mutation at mouse ESTR loci.;Four gene mutations were studied; p53, PARP-1, XPC and polkappa. The analysis of p53 deficient mice demonstrated that p53 status, therefore p53-depdnent apoptosis in mice has no effect on the spontaneous or radiation induced ESTR mutation rates, indicating p53 has no influence on ESTR stability and therefore has no role in the mechanisms of mutation acting at these loci. Three DNA repair deficient mice strain have been analysed (PARP-1, XPC and polkappa) and it was seen that in all three strains the spontaneous ETR mutation rates were elevated when compared to wild-type counterparts. This has led to the proposal that delay or lack of repair could lead to polymerase slippage due to enhanced replication fork pausing. From this study it has been suggested that the mechanism of mutation at ESTR loci is polymerase slippage due to replication fork pausing, similar to the mechanism proposed for microsatellites.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available