Biological responses to DNA damage, mutagenesis and tumorigenesis
Mutations contribute to genetic diversity and evolution. Mutations in somatic cells, especially those in stem cells, may lead to abnormalities in proliferation, differentiation, homeostasis and tissue function. Some mutations, when occurring in the right combination and in the right temporal order, will lead to the formation of cancer. We are characterizing the mechanisms by which somatic mutations are generated and accumulated in vivo, using mice as a model organism. We are also examining the biological mechanisms that underlie the development and progression of tumors, especially lymphomas and intestinal adenomas, in cancer-prone mouse models.
DNA repair and somatic mutation
Cells will frequently encounter numerous types of DNA lesions, such as base damage, mismatches, single-strand breaks and double-strand breaks. Various sophisticated DNA repair pathways have been evolved to deal with those DNA lesions. What would happen if a DNA repair pathway is defective or absent? We are determining the genetic consequences, in terms of somatic mutation and tumorigenesis, caused by defective DNA repair pathways in vivo. Our studies showed that somatic mutations are accumulated differentially in different cell types in vivo. We are determining whether the pathways and the activities of DNA repair are varied with developmental stages and cell types, and thus contribute to the differential accumulation.
Cell death as a safeguard of genome stability
DNA damage, shortened telomeres or inappropriate activation of oncogenes can all induce cell death, by the means of apoptosis or senescence. Cells harboring such misshapenness, if not eliminated, are at a great risk of accumulating new mutations and turning into preneoplastic cells. Therefore, although cell death may cause tissue injury or aging, it serves as a safeguard against mutagenesis and tumorigenesis. The somatic mutations that arise in experimental conditions of reduced or enhanced cell death are being characterized. Findings from such studies will provide important insights into the mechanisms underlying tumor initiation.
Genetic factors in the modulation of tumorigenesis in ApcMin mice
Patients of familial adenomatous polyposis (FAP) and ApcMin/+ mice, a model for FAP, develop adenomas at a high frequency in their intestines due to functional loss of APC, which negatively regulates Wnt signaling pathway. DNA hypomethylation, rendered by Dnmt1 mutation or by treatment with DNA demethylating agents, can suppress intestinal tumorigenesis in Apcmin/+ mice and in other cancer models. We are exploring the candidate factors that are responsible for the down regulation of Wnt/beta-catenin signaling pathway. Findings obtained from this model system may provide valuable clues to cancer prevention and cancer treatment.
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