Hypermutagenic induction of mitotic recombination by ionizing radiation in Mlhl null mouse cells Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/vh53x0196

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  • Mitotic recombination is a common autosomal mutation in mammalian cells involving crossover events between homologous chromosomes. This process can convert a cell with a heterozygous deficiency to one with a homozygous deficiency, and thus often represents the second step in tumor suppressor gene inactivation. In this study I examined the frequency and spectrum of ionizing radiation (IR)-induced autosomal mutations affecting Aprt activity in a mouse kidney cell line null for the Mlh1 mismatch repair (MMR) gene. The mutant frequency results demonstrated a hypermutable response to JR and the spectral analysis revealed that most of this response was due to the induction of mitotic recombinational events. High frequency induction of mitotic recombination was not observed in a DNA repair-proficient cell line or a cell line with an MMR-independent mutator type. I also provide evidence that JR exposure did not induce significant numbers of base-substitution in the Mlh1 null cells. These results demonstrate that IR exposure can initiate a process leading to mitotic recombinational events and that MMR function suppresses these events. My results suggest a caveat for use of IR to treat MMR deficient tumors because the combination of high levels of induced mitotic recombinational events and preexisting intragenic mutations might increase malignant potential in surviving cells.
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