The Telomere Anti-Checkpoint Activity

端粒反检查点活动

• 批准号: 1908875
• 负责人: Kurt Runge
• 金额: $ 87.5万
• 依托单位: Cleveland Clinic Foundation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1908875&HistoricalAwards=false
• 关键词: Telomere; Anti; Checkpoint; Activity

The DNA of multicellular organisms is packaged into linear chromosomes. The goal of this project is to understand how cells deal with DNA breaks, specifically how breaks near the ends of linear chromosomes are treated differently from breaks in other locations. The outcomes will help clarify why breaks near the ends of chromosomes do not trigger a DNA damage response while those at other locations do, and how this differential treatment maintains genome integrity. The project will offer research training and career development opportunities for graduate and undergraduate students, and a post-doctoral scientist, particularly aimed at increasing diversity in the STEM workforce. Results from the project will also be integrated into coursework in order to teach students current concepts of genomic stability.A fundamental question in the field of chromosome biology is why telomeres, the ends of linear eukaryotic chromosomes, are stable while internal double-strand breaks are not. DNA double-strand breaks promote genomic instability by DNA recombination and cause growth arrest by activating cell cycle checkpoints, but telomeres are stable and allow continuous cell growth. Telomeres are composed of DNA repeat tracts bound by specific proteins that "cap" the chromosome end to prevent its degradation and block checkpoint activation. This project will investigate how telomeres accomplish these functions by using an inducible telomere formation system that leverages powerful molecular genetics tools in the Schizosaccharomyces pombe model system. The specific hypothesis to be tested is whether S. pombe telomeres recruit effectors that post-translationally modify checkpoint proteins to block DNA damage signaling. Known candidate proteins will be tested and new candidate proteins will be sought by proteomic approaches in a comprehensive approach to identify the effectors of DNA damage checkpoint suppression at telomeres. The project will offer research training for graduate and undergraduate students, and a post-doctoral scientist, and project outcomes will be integrated into coursework.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.

多细胞生物的DNA包装成线性染色体。该项目的目的是了解细胞如何处理DNA断裂，特别是在线性染色体末端附近的断裂与其他位置的断裂不同。结果将有助于阐明为什么在其他位置的染色体末端附近的断裂不会触发DNA损伤反应，以及这种差异处理如何保持基因组完整性。该项目将为研究生和本科生提供研究培训和职业发展机会，以及一位博士后科学家，尤其是为了增加STEM劳动力的多样性。该项目的结果还将集成到课程中，以教学学生当前的基因组稳定性概念。染色体生物学领域的基本问题就是为什么端粒（线性真核染色体的末端）稳定的，而内部双段断裂则不是为什么。 DNA双链断裂通过DNA重组促进基因组不稳定性，并通过激活细胞周期检查点引起生长停滞，但端粒稳定并允许连续的细胞生长。端粒由由特定蛋白结合的DNA重复区组成，这些蛋白“ cap”染色体末端，以防止其降解和阻止检查点激活。该项目将通过使用可诱导的端粒形成系统来研究端粒如何完成这些功能，该系统利用Schizosaccharomyces Pombe模型系统利用强大的分子遗传学工具。要测试的具体假设是pombe端粒型招募效应子是否在翻译后修改检查点蛋白以阻止DNA损伤信号传导。将测试已知的候选蛋白质，并以蛋白质组学方法的全面方法来寻求新的候选蛋白质，以识别端粒抑制DNA损伤检查点的效应子。该项目将为研究生和本科生提供研究培训，并提供博士后科学家，项目成果将纳入课程工作。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响审查标准进行评估的支持。

项目成果

Ccq1 restrains Mre11-mediated degradation of short telomeres

Ccq1 抑制 Mre11 介导的短端粒降解

• DOI: 10.21203/rs.3.rs-1456395
• 发表时间: 2022
• 期刊: Research square
• 作者: Audry, J.;Runge, K.
• 通讯作者: Runge, K.

Telomere-binding proteins Taz1 and Rap1 regulate DSB repair and suppress gross chromosomal rearrangements in fission yeast

• DOI: 10.1371/journal.pgen.1008335
• 发表时间: 2019-08-01
• 期刊: PLOS GENETICS
• 影响因子: 4.5
• 作者: Irie, Hiroyuki;Yamamoto, Io;Ishikawa, Fuyuki
• 通讯作者: Ishikawa, Fuyuki

GGCX mutants that impair hemostasis reveal the importance of processivity and full carboxylation to VKD protein function

损害止血的 GGCX 突变体揭示了持续合成和完全羧化对 VKD 蛋白功能的重要性

• DOI: 10.1182/blood.2021014275
• 发表时间: 2022
• 期刊: Blood
• 影响因子: 20.3
• 作者: Rishavy, Mark A;Hallgren, Kevin;Wilson, Lee A;Hiznay, James M.;Runge, Kurt W;Berkner, Kathleen L
• 通讯作者: Berkner, Kathleen L