THE ROLE OF TELOMERASE REGULATORS IN TELOMERE MAINTENANCE AND GENOMIC INSTABILITY

端粒酶调节剂在端粒维持和基因组不稳定中的作用

基本信息

批准号：
10321969
负责人：
Alison A Bertuch
金额：
$ 46.32万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321969
关键词：
Adopted Affect Animal Model Biogenesis Biological Assay Biology CRISPR/Cas technology Cancer Cell Growth Cancer Etiology Cell Cycle Cell model Cells Chronic Lymphocytic Leukemia Complement Complex DNA DNA Damage DNA Folding DNA biosynthesis Data Development Dyskeratosis Congenita Fluorescence Functional disorder Genomic Instability Grant Growth Holoenzymes Human Investigation Knock-out Lead Length Libraries Link Malignant Neoplasms Mammalian Chromosomes Mediating Methods Molecular Molecular Conformation Mus Mutation Names Oncogenic Open Reading Frames Pathway interactions Patients Physiological Predisposition Proteins RNA Cap-Binding Proteins Regulation Role Study models Telomerase Telomere Capping Telomere Maintenance Telomere Shortening Telomere-Binding Proteins Validation Work Xenograft Model base cancer cell cancer diagnosis cancer therapy effective therapy follow-up genetic regulatory protein genome wide screen melanoma mutant new therapeutic target novel overexpression prevent promoter screening telomere telomere loss therapeutic target trafficking treatment strategy tumor tumor growth whole genome

项目摘要

Project Summary Mammalian chromosome ends or telomeres are tightly regulated by the telomerase that mediates telomere elongation and telomere-binding proteins that cap and protect telomere ends. Telomere DNA normally adopts a closed conformation, capped and protected by a multitude of telomere-binding proteins, to prevent DNA damage and genome instability. Telomeres become open and linear during DNA replication to enable telomerase access for telomere elongation. Exposed and critically short telomeres, as a result of mutations in telomerase and telomere regulators, also become open and susceptible to damage and genome instability, ultimately leading to cancer. Mutations in telomere-binding proteins and the TERT promoter have been identified in a number of cancers. Most cancer cells have up-regulated telomerase expression and activities, and cancer cells appear highly sensitive to perturbations in telomerase activities and telomere capping, making the telomerase attractive for therapeutic targeting. A comprehensive study of telomerase regulators therefore should greatly facilitate our understanding of telomerase dysregulation in cancer and the discovery of new drug targets. We have developed an arrayed whole-genome protein interaction network screening strategy based on the Bi-molecular Fluorescence Protein Complementation (BiFC) assay. A pilot TERT BiFC screen identified several proteins as key components of the telomerase complex, including a protein we named TARP1 that has never been characterized before. We propose here to screen genome wide for cell cycle-dependent regulators of the telomerase, and to examine the mechanisms and function of the TARP1-telomerase complex. We will use inducible TARP1 knockout cells generated by CRISPR/Cas9 as well as mouse xenograft models for these studies. Our work will have important implications in devising effective treatment strategies for cancers that result from telomere dysfunction induced genome instability.

项目概要哺乳动物染色体末端或端粒受到介导端粒酶的严格调节端粒延长和端粒结合蛋白覆盖和保护端粒末端。端粒DNA 通常采用封闭构象，由多种端粒结合蛋白加帽和保护，防止 DNA 损伤和基因组不稳定。 DNA 复制过程中端粒变得开放且呈线性使端粒酶能够进入端粒延长。暴露的端粒和极短的端粒，由于端粒酶和端粒调节因子的突变也变得开放并容易受到损伤和基因组影响不稳定，最终导致癌症。端粒结合蛋白和 TERT 启动子的突变已在多种癌症中被发现。大多数癌细胞端粒酶表达上调活性，癌细胞似乎对端粒酶活性和端粒的扰动高度敏感封端，使端粒酶对治疗靶向具有吸引力。端粒酶的综合研究因此，监管者应该极大地促进我们对癌症和端粒酶失调的理解发现新的药物靶点。我们开发了阵列式全基因组蛋白质相互作用网络基于双分子荧光蛋白互补（BiFC）测定的筛选策略。一名飞行员 TERT BiFC 筛选鉴定了几种蛋白质作为端粒酶复合物的关键成分，包括我们将其命名为 TARP1 的蛋白质，该蛋白质以前从未被表征过。我们在此建议进行全基因组筛查用于细胞周期依赖性端粒酶调节剂，并检查端粒酶的机制和功能 TARP1-端粒酶复合体。我们还将使用 CRISPR/Cas9 生成的诱导型 TARP1 敲除细胞作为这些研究的小鼠异种移植模型。我们的工作将对设计有效的端粒功能障碍引起的基因组不稳定导致的癌症的治疗策略。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effective gene editing by high-fidelity base editor 2 in mouse zygotes.

通过高保真碱基编辑器 2 在小鼠受精卵中进行有效的基因编辑。

DOI：
发表时间：
2017-08
期刊：
影响因子：
21.1
作者：
Liang, Puping;Sun, Hongwei;Sun, Ying;Zhang, Xiya;Xie, Xiaowei;Zhang, Jinran;Zhang, Zhen;Chen, Yuxi;Ding, Chenhui;Xiong, Yuanyan;Ma, Wenbin;Liu, Dan;Huang, Junjiu;Songyang, Zhou
通讯作者：
Songyang, Zhou

Glycerol kinase-like proteins cooperate with Pld6 in regulating sperm mitochondrial sheath formation and male fertility.

甘油激酶样蛋白与 Pld6 协同调节精子线粒体鞘形成和男性生育力。

DOI：
发表时间：
2017
期刊：
影响因子：
33.5
作者：
Chen, Yuxi;Liang, Puping;Huang, Yan;Li, Minyan;Zhang, Xiya;Ding, Chenhui;Feng, Junyan;Zhang, Zhen;Zhang, Xueqing;Gao, Yuanzhu;Zhang, Qinfeng;Cao, Shanbo;Zheng, Haiyan;Liu, Dan;Songyang, Zhou;Huang, Junjiu
通讯作者：
Huang, Junjiu

Phosphorylation of PLIN3 by AMPK promotes dispersion of lipid droplets during starvation.

AMPK 磷酸化 PLIN3 可促进饥饿期间脂滴的分散。

DOI：
发表时间：
2019
期刊：
影响因子：
21.1
作者：
Zhu, Jianxi;Xu, Mingyang;Liu, Yi;Zhuang, Lisha;Ying, Kejun;Liu, Feng;Liu, Dan;Ma, Wenbin;Songyang, Zhou
通讯作者：
Songyang, Zhou