Multifaceted regulation of the DNA repair machinery and suppression of aberrant transcription by telomere proteins

DNA 修复机制的多方面调控和端粒蛋白异常转录的抑制

• 批准号: 2246561
• 负责人: Neal Lue
• 金额: $ 91万
• 依托单位: Joan and Sanford I. Weill Medical College of Cornell University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2246561&HistoricalAwards=false
• 关键词: Multifaceted; regulation; DNA; repair; machinery

At the ends of chromosomes, structures known as telomeres play an important role in protecting the integrity of genetic information contained in DNA. Telomeres can be likened to aglets, the caps at the tips of shoelaces; when the aglets are missing, the shoelaces (chromosomes) get frayed and fall apart. Many proteins work together to protect telomere DNA, and defects in these proteins can lead to chromosome destabilization. This study will provide insights into abnormal transactions at telomeres and improve understanding of how genetic information is protected. This project will also provide opportunities for training many community college students in the technical and critical thinking skills necessary for future scientific careers, and therefore have broadly beneficial impacts on society.Telomeres are specialized nucleoprotein structures that allow cells to distinguish normal chromosome ends from double strand breaks. When these structures are defective, telomere DNA becomes deprotected and is subjected to abnormal “repair” reactions, which can include degradation, recombination, and end-to-end fusion. Our understanding of the factors that mediate and regulate abnormal telomere repair is incomplete. For example, abnormal telomeres are often transcribed at high levels, and both the mechanisms of transcription and the functional significance of the transcripts are poorly understood. This study will address two major questions. First, how are abnormal telomere repair pathways regulated by the cell cycle? Second, what factors are involved in abnormal telomere transcription and how do the transcripts impact abnormal telomere repair? The project will combine biochemical and molecular genetic approaches to address these questions in the fungus Ustilago maydis (a maize pathogen) that has well-developed genetic tools and significant similarities to animal cells with respect to telomere regulation. The outcomes will advance our understanding of mechanisms that underlie abnormal repair reactions at deprotected telomeres.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在染色体的末端，被称为端粒的结构在保护DNA中包含的遗传信息的完整性方面起着重要作用。端粒可以被比作肩带，鞋带顶端的帽子；当肩带丢失时，鞋带（染色体）就会磨损并脱落。许多蛋白质共同保护端粒DNA，这些蛋白质的缺陷会导致染色体不稳定。这项研究将提供对端粒异常交易的见解，并提高对遗传信息如何被保护的理解。该项目还将为许多社区大学学生提供培训机会，使他们具备未来科学事业所需的技术和批判性思维技能，从而对社会产生广泛的有益影响。端粒是一种特殊的核蛋白结构，它使细胞能够区分正常的染色体末端和双链断裂。当这些结构有缺陷时，端粒DNA就会失去保护，并发生异常的“修复”反应，包括降解、重组和端到端融合。我们对介导和调节异常端粒修复的因素的理解是不完整的。例如，异常的端粒通常是高水平的转录，转录的机制和转录的功能意义都知之甚少。这项研究将解决两个主要问题。首先，异常的端粒修复途径是如何被细胞周期调节的？第二，哪些因素参与异常端粒转录，转录物如何影响异常端粒修复？该项目将结合生物化学和分子遗传学方法来解决真菌麦氏黑穗病菌（一种玉米病原体）的这些问题，这种真菌具有发达的遗传工具，并且在端粒调控方面与动物细胞有显著的相似性。这些结果将促进我们对脱保护端粒异常修复反应机制的理解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。