(PQA2) Impact of obesity on endogenous mutational hotspots

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DESCRIPTION (provided by applicant): The overall objective of this proposal is to understand how dietary energy balance and especially obesity influences genome stability at endogenous mutational "hotspots". To achieve this objective, we will use a novel mouse model to determine the impact of obesity on DNA structure-induced mutagenesis in various tissues from these mice. Repetitive DNA sequences are widely dispersed throughout mammalian genomes and can adopt alternative (non-B DNA) secondary structures, such as H-DNA. Importantly, these non-B DNA structure- forming sequences often co-localize with endogenous mutational "hotspots" in the human genome, implicating them in cancer etiology. For example H-DNA-forming sequences in the c-MYC gene are found at translocation breakage "hotspots" in Burkitt's lymphoma and acute B-cell lymphoma. We have developed novel mutation- reporter mice containing a human H-DNA-forming c-MYC sequence that co-localizes with a translocation breakpoint "hotspot" in Burkitt's lymphoma, and demonstrated for the first time that these sequences are mutagenic in living animals. Obesity is known to increase cellular oxidative stress and oxidative DNA damage, whereas calorie restriction has been shown to decrease cellular oxidative stress, oxidative DNA damage, reduce mutagenesis and to enhance DNA repair pathways. In addition, obesity is an important risk factor for a significant number of cancers in both men and women, including leukemias and lymphomas. However, the extent to which dietary energy balance and especially obesity influences DNA structure-induced genetic instability is not known. Thus, a goal of the proposed work is to fill this gap in knowledge. In ths proposal, we will test the working hypothesis that obesity increases DNA structure-induced genetic instability. We will examine the impact of diet-induced obesity (DIO) on DNA structure-induced mutagenesis in our novel mutation reporter mice. Several different tissues will be evaluated from these mice to determine whether there are any tissue specific differences in response to DIO. We will also explore potential mechanisms for any observed effects of obesity on DNA structure-induced genetic instability. We will focus our studies on the impact of obesity on DNA repair mechanisms as several recent studies have suggested that obesity impairs multiple DNA repair pathways, including non-homologous end-joining, a repair pathway that we have found to play a role in the processing of H-DNA structures in mammalian cells. Completion of the proposed studies will lead to a greater understanding of how obesity influences cancer development. In addition, this work will lead to the identification of novel targets for the prevention and/or treatment of obesity-related cancers.