Epigenetic Regulation of Drosophila Telomere Function

果蝇端粒功能的表观遗传调控

• 批准号: 8258779
• 负责人: Michael H Brodsky
• 金额: $ 32.65万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258779
• 关键词: Address; Aging; Animal Model; Ataxia-Telangiectasia-Mutated protein kinase; Binding; Biochemical; Biology; Categories; Cells; Chromatin; Chromosomal Breaks; Chromosomes; Complex; DNA; DNA Damage; Data; Defect; Drosophila genus; Drosophila melanogaster; Employee Strikes; Epigenetic Process; Frequencies; Genes; Genetic; Genome; Heterochromatin; Human; Lead; Learning; Link; Malignant Neoplasms; Mediating; Modeling; Mutation; Pathway interactions; Phosphotransferases; Play; Process; Proteins; Recruitment Activity; Regulation; Role; Saccharomycetales; Sequence-Specific DNA Binding Protein; Site; Staining method; Stains; Telomere Maintenance; Telomere Pathway; Testing; base; cell type; chromosome replication; histone methyltransferase; improved; mutant; research study; response; telomere

A central question in eukaryotic chromosome biology is how the normal ends of linear chromosomes, telomeres, are distinguished from double strand breaks. One well-established mechanism is the recognition of telomeric-specific sequences by sequence specific DNA binding proteins such as human TRF2. However, several observations demonstrate that other mechanisms play an essential, but poorly understood role in telomere protection. Among the most striking examples are studies in Drosophila in which it is possible to isolate and maintain chromosomes with no telomere-specific sequences at their ends. These studies indicate that a sequence-independent, i.e. epigenetic, mechanism regulates telomere protection in Drosophila. Two cellular pathways have been implicated in Drosophila telomere protection. The chromatin- associated protein HP1 and a telomere-specific binding partner, HOAP, are localized to telomeres and are required for their protection. We have also found that mutations in the DNA damage response kinases ATM and ATR lead to loss of telomeric HP1-HOAP and loss of telomere protection. Recognition of chromosome ends by ATM/ATR kinases could provide a sequence-independent means to recruit proteins to telomeres, but this model does not address how these proteins distinguish between chromosome breaks and telomeres. We hypothesize that DNA damage response pathways act in a homeostatic mechanism to protect telomeres by recruiting HP1-HOAP complexes to incompletely protected telomeres. To test this model, we will probe the activity of ATM/ATR kinases at normal telomeres and at telomeres with defective HP1 spreading. In addition, our preliminary results suggest that the mutator-2 gene may act as a link between the DNA damage response pathway and HP1, but that it also has a second function fusing telomeres when they become completely unprotected. By understanding the role of mutator-2 at telomeres, we may learn how the damage response is modulated at telomeres and at chromosome breaks. Telomeres appear to play a central role in human cancer and aging. These studies will help elucidate a new category of epigenetic inheritance - sequence-independent regulation of telomere function. Given that both HP1 and DNA damage response pathways play roles at human telomeres, understanding telomere function in Drosophila may lead to new ways to shorten or extend telomeres in humans.

真核染色体生物学的一个中心问题是线性染色体的正常末端如何， 端粒与双链断裂不同。一项完善的机制是 通过序列特异性 DNA 结合蛋白（例如人类）识别端粒特异性序列 TRF2。然而，一些观察结果表明，其他机制发挥着重要作用，但效果不佳。 了解端粒保护中的作用。最引人注目的例子是对果蝇的研究 可以分离和维持在其染色体上没有端粒特异性序列的染色体 结束。这些研究表明，一种与序列无关的（即表观遗传）机制调节 果蝇端粒保护。 两种细胞途径与果蝇端粒保护有关。染色质- 相关蛋白 HP1 和端粒特异性结合伴侣 HOAP 定位于端粒并 需要他们的保护。我们还发现DNA损伤反应中的突变 激酶 ATM 和 ATR 导致端粒 HP1-HOAP 丢失和端粒保护丧失。 ATM/ATR 激酶对染色体末端的识别可以提供一种独立于序列的方法 将蛋白质招募到端粒，但该模型没有解决这些蛋白质如何区分 染色体断裂和端粒之间。我们假设 DNA 损伤反应途径 通过招募 HP1-HOAP 复合物以稳态机制发挥作用来保护端粒 端粒保护不完全。 为了测试这个模型，我们将探测 ATM/ATR 激酶在正常端粒和端粒处的活性 HP1 传播有缺陷。此外，我们的初步结果表明mutator-2基因可能 作为 DNA 损伤反应途径和 HP1 之间的纽带，但它还有第二个 当端粒完全不受保护时，它们就会发挥融合端粒的作用。通过了解角色 mutator-2 在端粒上，我们可以了解如何在端粒处调节损伤反应 染色体断裂。 端粒似乎在人类癌症和衰老中发挥着核心作用。这些研究将有助于阐明 表观遗传的新类别——端粒功能的序列独立调节。给定 HP1 和 DNA 损伤反应途径都在人类端粒中发挥作用，了解 果蝇的端粒功能可能会带来缩短或延长人类端粒的新方法。