The interplay of the CST complex and telomerase at human telomeres

项目摘要/摘要 这一建议是R35CA210036的补充，R35CA210036关注的是端粒在癌症中的作用，有三个 特别强调的领域：1。端粒肿瘤抑制通路的分子机制； 2.端粒功能障碍在癌症发展过程中引起的基因组不稳定；3.利用 端粒生物学，以获得对53BP1介导的DSB修复的更深入的了解。此R50请求以下项目的薪资支持 高井博之博士，他是单位主任实验室的一名高生产率的长期研究专家。 自2002年以来，高井博士一直是单位主任实验室的关键成员。他的主要兴趣是 癌症的基因组不稳定性始于他对ATR和ATM的Chk1和Chk2效应激酶的研究 DNA损伤信号通路。在德兰格实验室，高井博士发现马厩 ATR和ATM激酶以及所有其他PI3K相关激酶的表达需要TEL2，他展示了这一点 充当监护人(Takai等人单元格2007)。在第二个突破中，高井博士第一个证明了 这些细胞检测到功能失调的端粒为双链断裂(DSB)，激活ATM激酶和 在染色体末端积累DNA损伤反应因子。高井博士检测端粒的方法 损害已成为该领域的标准化验(Takai等人)。货币。Biol 2003)，他的发现解释了 端粒缩短在癌症中的作用。在端粒酶激活之前，端粒磨损施加了一种 当端粒过短激活DNA损伤时，早期癌症发展中的增殖障碍 反应并诱导衰老或细胞凋亡。最近，Takai博士把重点放在了分子 端粒缩短的机制。端粒缩短的部分原因是DNA复制不能 复制线性DNA的末端。然而，端粒磨损的最大因素是端粒的5‘端切除 在它们复制后结束，这是产生保护性3‘端粒突出物所需的过程。在这之后 过程中，端粒上过度的5‘端切除被Pola/Primase介导的填充合成(Wu， Takai和De Lange，细胞2012)。Takai博士证明Pola/Primase通过端粒被招募 其辅助因子CST与端粒保护素复合体的相互作用。高井博士接下来展示了 缺乏CST/Pola/Primase，未减轻的切除会导致5‘端链随机缩短和 端粒丢失(Takai等人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。 实验室确定了CST/Pola/Primase在DSB修复中的类似作用(Zman等人自然界 2018年)。作为单位主任小组的长期成员和高技能、严谨、创造性和协作性强的 作为一名科学家，高井博士是R35研究计划的关键贡献者。Takai博士高度致力于该单位 主任对端粒在癌症中的作用的研究和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，R35取得了成功。

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.