DNA Repair and Aging in Drosophila

项目摘要 我们的目标是了解细胞如何修复双链DNA断裂，并特别强调这一点 修复过程与老化有关。最近的研究表明，果蝇的衰老与 生殖细胞中双链断裂(DSB)的修复方式发生了显著变化。例如，较旧的 男性60%以上的DSB使用同源修复途径，而男性使用同源修复途径的DSB不到14% 年轻的雄性。实验将确定这些变化是否是更普遍现象的一部分 将老化与细胞“选择”使用哪种DSB修复机制联系起来。这些实验利用了一种 一个测试良好的系统，称为“修复报告3”(Rr3)，用于衡量单个DSB修复的相对使用率 果蝇中的路径。需要回答的具体问题包括： 与年龄相关的变化是否延伸到体细胞？ 这种情况在两性中都存在吗？ 在基因组中的任何地方，DSB是否存在相同的年龄相关模式？ 这些变化可以用特定的模型来解释吗，包括干细胞再生或组蛋白 乙酰化？ 延长寿命的突变是否也会改变与年龄相关的DSB修复？ 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DSB，被认为是维持DNA损伤稳定的关键 基因组。人类DSB修复基因突变的表型包括过早衰老， 放射敏感性、免疫缺陷和癌症易感性。这些实验将有助于 了解DSB修复，特别是其与老化过程的关系。

Project Summary The goal is to understand how cells repair double-strand DMA 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. For example, older males used a homologous repair pathway for more than 60% of their DSBs compared to less than 14% for young males. Experiments 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: ¿ Do the age-related changes extend to the somatic cells? ¿ Do they occur in both sexes? ¿ Is the same age-specific pattern seen for DSBs formed anywhere in the genome? ¿ Can these changes be explained by specific models, including stem cell regeneration or histone acetylation? ¿ Do mutations which extend lifespan also modify age-related DSB repair? ¿ 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.