DNA Repair and Aging in Drosophila

描述(申请人提供)：目标是了解细胞如何修复双链DNA断裂，特别强调这种修复过程是如何与衰老相关的。最近的研究表明，果蝇的衰老与生殖细胞中双链断裂(DSB)修复方式的显著变化有关。老年男性超过60%的DSB使用了相应的修复途径，而年轻男性使用的修复途径更快、更容易出错，而年轻男性使用的修复途径不到14%。这个项目将确定这些变化是否是一个更普遍的现象的一部分，将老化与细胞使用哪种DSB修复机制的“选择”联系在一起。这些实验使用了一种经过良好测试的系统，名为“修复报告3”(Rr3)，用来测量果蝇个体DSB修复途径的相对使用率。需要回答的具体问题是：1.与年龄相关的变化是否延伸到体细胞？2.它们是否发生在两性身上？3.在基因组中的任何地方是否存在相同的年龄相关模式？4.这些变化是否可以用特定的模型来解释，包括干细胞再生或组蛋白乙酰化？5.延长寿命的突变和膳食补充剂(白藜芦醇)是否也改变了与年龄相关的DSB修复？6.某些DSB修复突变如何影响修复途径的选择？相关性：DNA损伤的修复，特别是双链断裂，被认为是维持基因组稳定的关键。人类DSB修复基因突变具有早衰、辐射敏感性、免疫缺陷和癌症易感性等表型。这些实验将有助于理解DSB修复，特别是它与衰老过程的关系。

DESCRIPTION (provided by applicant): The goal is to understand how cells repair double-strand DNA breaks with special emphasis on how this repair process is related to aging. Recent work has revealed that aging in Drosophila is correlated with pronounced changes in how double-strand breaks (DSBs) are repaired in the germ cells. Older males used a homologous repair pathway for more than 60% of their DSBs compared to less than 14% for young males where faster, more error-prone, pathways predominate. This project will determine whether these changes are part of a more general phenomenon linking aging with the cell's "choice" of which DSB repair mechanism to use. The experiments make use of a well-tested system called "Repair reporter 3" (Rr3) to measure the relative usage of individual DSB repair pathways in Drosophila. Specific questions to be answered are: 1. Do the age-related changes extend to the somatic cells? 2. Do they occur in both sexes? 3. Is the same age-specific pattern seen for DSBs formed anywhere in the genome? 4. Can these changes be explained by specific models, including stem cell regeneration or histone acetylation? 5. Do mutations and dietary supplements (resveratrol) which extend lifespan also modify age-related DSB repair? 6. How do certain DSB repair mutations affect the choice of repair pathway? Relevance: Repair of DNA damage, especially DSBs, is recognized as crucial to maintaining the stability of the genome. Human mutations in DSB repair genes have phenotypes including premature aging, radiosensitivity, immunodeficiency and cancer predisposition. These experiments will contribute to the understanding of DSB repair, especially its relationship to the aging process.