(PQA2) Impact of obesity on endogenous mutational hotspots

(PQA2) 肥胖对内源突变热点的影响

• 批准号: 8841331
• 负责人: John DiGiovanni
• 金额: $ 16.8万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841331
• 关键词: Acute; Adopted; Affect; Animals; B-Cell Lymphomas; B-DNA; Brain; Burkitt Lymphoma; Caloric Restriction; Cancer Etiology; Chromosome Breakage; DNA; DNA Damage; DNA Double Strand Break; DNA Maintenance; DNA Repair; DNA Repair Pathway; DNA Sequence; DNA Structure; DNA strand break; Development; Diet; Double Strand Break Repair; Event; G-Quartets; Genetic; Genome; Genome Stability; Genomic Instability; Goals; Guanine; H-DNA; Health; Human; Human Genome; Knowledge; Lead; Life; Liver; MYC gene; Malignant Neoplasms; Mammalian Cell; Mus; Mutagenesis; Mutation; Nonhomologous DNA End Joining; Obesity; Obesity associated cancer; Oxidative Stress; Pathway interactions; Play; Positioning Attribute; Predisposition; Prevention; Process; Public Health; Reactive Oxygen Species; Refractory; Reporter; Research; Risk; Risk Factors; Role; Running; Skin; Structure; Testing; Time; Tissues; Translocation Breakpoint; Woman; Work; cancer risk; cancer type; energy balance; leukemia/lymphoma; mammalian genome; men; mouse model; novel; novel strategies; oxidative DNA damage; prevent; repaired; research study; response

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.

描述（由申请人提供）：本提案的总体目标是了解饮食能量平衡，特别是肥胖如何影响内源性突变“热点”的基因组稳定性。为了实现这一目标，我们将使用一种新的小鼠模型来确定肥胖对这些小鼠各种组织中DNA结构诱导突变的影响。重复DNA序列广泛分布在哺乳动物基因组中，并可采用替代（非b DNA）二级结构，如H-DNA。重要的是，这些非b DNA结构形成序列通常与人类基因组中的内源性突变“热点”共定位，暗示它们与癌症病因有关。例如，在伯基特淋巴瘤和急性b细胞淋巴瘤的易位断裂“热点”中发现了c-MYC基因中的h - dna形成序列。我们开发了一种新的突变报告小鼠，其中含有人类h - dna形成的c-MYC序列，该序列与伯基特淋巴瘤的易位断点“热点”共定位，并首次证明这些序列在活体动物中具有诱变性。众所周知，肥胖会增加细胞氧化应激和氧化DNA损伤，而卡路里限制已被证明可以减少细胞氧化应激、氧化DNA损伤、减少突变并增强DNA修复途径。此外，肥胖是导致包括白血病和淋巴瘤在内的大量男性和女性癌症的一个重要风险因素。然而，饮食能量平衡，特别是肥胖对DNA结构引起的遗传不稳定的影响程度尚不清楚。因此，提出的工作的目标是填补这一知识空白。在这个提议中，我们将测试肥胖增加DNA结构诱导的遗传不稳定性的工作假设。我们将在我们的新型突变报告小鼠中研究饮食诱导肥胖（DIO）对DNA结构诱导突变的影响。将对这些小鼠的几种不同组织进行评估，以确定对DIO的反应是否存在任何组织特异性差异。我们还将探索任何观察到的肥胖对DNA结构诱导的遗传不稳定的影响的潜在机制。我们将重点研究肥胖对DNA修复机制的影响，因为最近的几项研究表明，肥胖损害了多种DNA修复途径，包括非同源末端连接，这是一种我们发现在哺乳动物细胞中H-DNA结构加工中起作用的修复途径。这些研究的完成将有助于我们更好地了解肥胖是如何影响癌症发展的。此外，这项工作将导致确定预防和/或治疗肥胖相关癌症的新靶点。