The interplay of the CST complex and telomerase at human telomeres

人类端粒上 CST 复合物和端粒酶的相互作用

• 批准号: 10019486
• 负责人: Hiroyuki Takai
• 金额: $ 14.24万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019486
• 关键词: Apoptosis; Area; Biological Assay; Biology; Cells; Chromosomes; Companions; Complex; DNA; DNA Damage; DNA Primase; DNA biosynthesis; Development; Double Strand Break Repair; Excision; Functional disorder; Genomic Instability; Goals; Human; Knowledge; Laboratories; Malignant Neoplasms; Mediating; Methods; Molecular; Nature; Pathway interactions; Phosphotransferases; Process; Research; Role; Scientist; Signal Pathway; Specialist; Telomerase; Telomere Maintenance; Telomere Shortening; Tumor Suppressor Proteins; Wages; ataxia telangiectasia mutated protein; career; chaperonin; experimental study; innovation; insight; interest; member; p53-binding protein 1; programs; recruit; response; senescence; success; telomere; telomere loss

Project Summary/Abstract This proposal is a companion to R35CA210036, which is focused on the role of telomeres in cancer with three areas of particular emphasis: 1. The molecular mechanism underlying the telomere tumor suppressor pathway; 2. The genome instability caused by telomere dysfunction in cancer development; and 3. The opportunity to use telomere biology to gain deeper insights into 53BP1-mediated DSB repair. This R50 requests salary support for Dr. Hiroyuki Takai, who is a highly productive long-term Research Specialist in the Unit Director’s laboratory. Dr. Takai has been a key member of the Unit Director’s laboratory since 2002. His main interest in genome instability in cancer started with his studies of the Chk1 and Chk2 effector kinases of the ATR and ATM DNA damage signaling pathways, respectively. In the de Lange lab, Dr. Takai discovered that the stable expression of the ATR and ATM kinases as well as all other PI3K-related kinases requires Tel2, which he showed acts as a chaperonin (Takai et al. Cell 2007). In a second breakthrough, Dr. Takai was the first to demonstrate that cells detect dysfunctional telomeres as Double-strand Breaks (DSBs), activating the ATM kinase and accumulating DNA damage response factors at chromosome ends. Dr. Takai’s method for detecting telomere damage has become the standard assay the field (Takai et al. Curr. Biol 2003) and his findings explained the role of telomere shortening in cancer. Prior to the activation of telomerase, telomere attrition imposes a proliferative barrier during early cancer development when critically short telomeres activate the DNA damage response and induce senescence or apoptosis. More recently, Dr. Takai has focused on the molecular mechanism of the telomere shortening. Telomere shortening derives in part from the inability of DNA replication to copy the ends of linear DNAs. However, the greatest factor in telomere attrition is the 5’ resection of telomere ends after their replication, a process needed to generate the protective 3’ telomeric overhangs. After this process, excessive 5’ end resection at telomeres is counteracted by Pola/Primase mediated fill-in synthesis (Wu, Takai, and de Lange, Cell 2012). Dr. Takai showed that Pola/primase is recruited to telomeres through the interaction of its accessory factor, CST, with the telomeric shelterin complex. Dr. Takai next showed that in absence of CST/Pola/primase, unmitigated resection leads to stochastic shortening of the 5’ ended strand and telomere loss (Takai et al. GenesDev 2016). Finally, Dr. Takai was instrumental in a study from the Unit Director’s laboratory establishing an analogous role for CST/Pola/primase in the repair of DSBs (Zirman et al. Nature 2018). A long-term member of the Unit Director’s group and a highly-skilled, rigorous, creative, and collaborative scientist, Dr. Takai is a pivotal contributor to the R35 research program. Dr. Takai is highly committed to the Unit Director’s research on the role of telomeres in cancer and his career goal is to continue to excel and support the success of the R35 through innovative and path-breaking research.

项目总结/摘要 该提案是R35 CA 210036的伴侣，R35 CA 210036专注于端粒在癌症中的作用， 特别强调的领域：1。端粒肿瘤抑制通路的分子机制; 2.癌症发展中端粒功能障碍引起的基因组不稳定性; 3.机会使用 端粒生物学以更深入地了解53 BP 1介导的DSB修复。此R50请求工资支持 博士高井博之，他是部门主管实验室的一名高产长期研究专家。 自2002年以来，Takai博士一直是该单位主任实验室的重要成员。他的主要兴趣是 癌症基因组的不稳定性始于他对ATR和ATM的Chk 1和Chk 2效应激酶的研究 DNA损伤信号通路。在德兰格的实验室里，高井博士发现， ATR和ATM激酶以及所有其他PI 3 K相关激酶的表达需要Tel 2，他表示， 作为伴侣蛋白（Takai et al. Cell 2007）。在第二个突破中，高井博士第一个证明了 细胞检测功能失调的端粒作为双链断裂（DSB），激活ATM激酶， 在染色体末端积累DNA损伤反应因子。高井博士的端粒检测方法 损伤已经成为该领域的标准测定法（Takai等人，Curr. Biol 2003）和他的研究结果解释了 端粒缩短在癌症中的作用在端粒酶激活之前，端粒的磨损使端粒酶活性降低。 当短端粒激活DNA损伤时，早期癌症发展过程中的增殖屏障 反应并诱导衰老或凋亡。最近，高井博士把重点放在分子水平上， 端粒缩短的机制。端粒缩短的部分原因是由于DNA不能复制 复制线性DNA的末端然而，端粒磨损的最大因素是端粒的5'切除 在它们复制后终止，这是产生保护性3'端粒突出端所需的过程。在此之后 在此过程中，端粒处的过量5 ′末端切除被Pola/Primase介导的填充合成抵消（Wu， Takai和de Lange，Cell 2012）。Takai博士表明，Pola/primase是通过端粒被招募的。 其辅助因子CST与端粒shelterin复合物的相互作用。高井博士接下来表明， 如果不存在CST/Pola/引发酶，则完全切除导致5'端链的随机缩短， 端粒缺失（Takai et al. GenesDev 2016）。最后，高井博士在单位主任的一项研究中发挥了重要作用。 一个实验室建立了CST/Pola/引发酶在DSB修复中的类似作用（Zirman等人，Nature 2018年）。长期担任单位主任组成员，具有高技能、严谨、创新、协作精神 作为一名科学家，Takai博士是R35研究计划的关键贡献者。高井博士对这个部门非常忠诚 主任对端粒在癌症中的作用的研究，他的职业目标是继续超越和支持 通过创新和开创性的研究取得了R35的成功。