DNA Repair and Aging in Drosophila

果蝇的 DNA 修复和衰老

• 批准号: 7897774
• 负责人: William R. ENGELS
• 金额: $ 54.4万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-07-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897774
• 关键词: Accounting; Address; Affect; Age; Aging; Aging-Related Process; Biological Assay; Cells; Chemicals; DNA Double Strand Break; DNA Repair; Data; Double Strand Break Repair; Drosophila genus; Exonuclease; Female; Funding; Genes; Genetic; Genome; Genome Stability; Genomics; Germ Cells; Goals; Heat-Shock Response; Histone Acetylation; Human; Immunodeficiency and Cancer; Individual; Length; Link; Location; Longevity; Measures; Modeling; Modification; Monitor; Mutation; Natural regeneration; Orthologous Gene; Pathway interactions; Pattern; Phenotype; Predisposition; Premature aging syndrome; Procedures; Process; Radiation Tolerance; Relative (related person); Reporter; Resveratrol; Site; Somatic Cell; Spermatogonia; Stem cells; System; Testing; Tissues; Werner Syndrome; Work; age effect; age related; base; chromatin modification; dietary supplements; endonuclease; male; overexpression; repaired; research study; sex; stem

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.

描述（由申请人提供）：目标是了解细胞如何修复双链DNA破裂，并特别强调该修复过程与衰老的关系。最近的工作表明，果蝇中的衰老与生殖细胞中双链断裂（DSB）修复的明显变化相关。年龄较大的男性使用了同源修复途径的DSB 60％以上，而年轻男性则不到14％，而男性更快，更容易出错，途径占主导地位。该项目将确定这些变化是否是将衰老与细胞的“选择”联系起来的更普遍现象的一部分。该实验利用了一个称为“ Repair Reporter 3”（RR3）的经过良好测试的系统来测量果蝇中单个DSB修复途径的相对使用。要回答的具体问题是：1。与年龄相关的变化是否扩展到体细胞？ 2。它们都出现在男女中吗？ 3。对于基因组中任何地方形成的DSB的同一年龄模式是否相同？ 4。这些变化是否可以通过特定模型来解释，包括干细胞再生或组蛋白乙酰化？ 5。延长寿命的突变和饮食补充剂（白藜芦醇）是否还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，尤其是DSB的修复对于维持基因组的稳定性至关重要。 DSB修复基因中的人类突变具有表型，包括过早衰老，放射敏性，免疫缺陷和癌症易感性。这些实验将有助于理解DSB修复，尤其是其与衰老过程的关系。