Epigenetic Regulation of Drosophila Telomere Function

果蝇端粒功能的表观遗传调控

• 批准号: 8065888
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065888
• 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; Health; 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

DESCRIPTION (provided by applicant): 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 by 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. PUBLIC HEALTH RELEVANCE: Telomeres, the normal ends of chromosomes, appear to play important roles in human aging and cancer. We are using the model organism Drosophila melanogaster to study how proteins that recognize damaged chromosomes also help regulate telomere function. Improved understanding of telomere regulation may provide new strategies to modulate human aging and cancer.

描述（由申请人提供）：真核染色体生物学的一个中心问题是如何区分线性染色体的正常末端（端粒）与双链断裂。一种成熟的机制是通过序列特异性 DNA 结合蛋白（例如人 TRF2）识别端粒特异性序列。然而，一些观察结果表明，其他机制在端粒保护中发挥着重要但人们知之甚少的作用。最引人注目的例子是果蝇的研究，其中可以分离和维持末端没有端粒特异性序列的染色体。这些研究表明，果蝇中的端粒保护是由序列无关的（即表观遗传）机制调节的。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，是端粒保护所必需的。我们还发现 DNA 损伤反应激酶 ATM 和 ATR 的突变会导致端粒 HP1-HOAP 的丢失和端粒保护的丧失。 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来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。我们假设 DNA 损伤反应途径通过稳态机制发挥作用，通过将 HP1-HOAP 复合物募集到不完全保护的端粒来保护端粒。为了测试这个模型，我们将探测正常端粒和 HP1 扩散缺陷端粒上 ATM/ATR 激酶的活性。此外，我们的初步结果表明，mutator-2 基因可能充当 DNA 损伤反应途径和 HP1 之间的纽带，但它还具有第二种功能，即当端粒完全不受保护时融合端粒。通过了解 mutator-2 在端粒上的作用，我们可以了解如何在端粒和染色体断裂处调节损伤反应。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，即端粒功能的序列独立调节。鉴于 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。公共卫生相关性：端粒是染色体的正常末端，似乎在人类衰老和癌症中发挥着重要作用。我们正在使用模式生物果蝇来研究识别受损染色体的蛋白质如何帮助调节端粒功能。对端粒调控的进一步了解可能会提供调节人类衰老和癌症的新策略。