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Mechanisms of Obesity-Induced Genetic Instability at Endogenous Mutation Hotspots

肥胖引起的内源突变热点遗传不稳定性的机制

基本信息

批准号：
10065499
负责人：
John DiGiovanni
金额：
$ 43.58万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065499
关键词：
Acute Adopted Animals B-Cell Lymphomas B-DNA Biological Assay Bone Marrow Burkitt Lymphoma Caloric Restriction Cancer Etiology DNA DNA Damage DNA Mutational Analysis DNA Repair DNA Repair Pathway DNA Sequence DNA Sequence Alteration DNA Structure DNA biosynthesis Data Development Diet Double Strand Break Repair Down-Regulation Gamma-H2AX Gender Generations Genetic Genome Genome Stability Genomic Instability Goals Guanine H-DNA Human Impairment Knowledge Lead Link Liver Malignant Neoplasms Mammals Maps Measures Mus Mutagenesis Mutation Nonhomologous DNA End Joining Obese Mice Obesity Obesity associated cancer Organism Oxidative Stress Pathway interactions Play Predisposition Prevention Process Public Health RTH-1 Nuclease Refractory Reporter Research Risk Factors Role Sampling Spleen Structure Testing Thymus Gland Time Tissues Transgenic Mice Transgenic Organisms Translocation Breakpoint Work Z-Form DNA c-myc Genes cancer genome cancer risk diet-induced obesity dietary dietary control dietary restriction energy balance experimental study genome integrity genomic tools homologous recombination in vivo leukemia/lymphoma mammalian genome mouse model novel novel strategies obesity risk obesity treatment oxidative DNA damage prevent public health relevance repaired response tool transcriptome sequencing

项目摘要

PROJECT SUMMARY The overall objective of this proposal is to understand how dietary energy balance and especially obesity influences genome stability at endogenous mutation “hotspots”. To achieve this objective, we will use novel mouse models that we have developed 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 and Z- DNA. Importantly, these non-B DNA structure-forming sequences are significantly enriched at endogenous mutation hotspots in human cancer genomes, 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 human H-DNA- and Z- DNA-forming sequences that co-localize with translocation breakpoint hotspots, and demonstrated for the first time that these sequences are mutagenic in vivo. 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. 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 this proposal, we will test the working hypothesis that obesity increases DNA structure-induced genetic instability. We will examine the impact of diet-induced obesity and calorie restriction on DNA structure-induced mutagenesis in mice. Several different tissues will be evaluated from these mice to determine whether there are any tissue specific differences in mutagenesis in response to energy balance manipulation. We will also explore mechanisms for the impact 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 non-B DNA. In addition, we have found that flap endonuclease 1 (FEN1) plays an important role in error-free processing of non-B DNA and that its levels are modulated by dietary energy balance. These observations will also be explored in more detail in this proposal. Completion of the proposed studies will lead to a greater understanding of how obesity influences cancer etiology. In addition, this work will lead to the identification of novel targets for the prevention and/or treatment of obesity-related cancers.

项目总结