Functional Determinants of Chromosome Segregation

染色体分离的功能决定因素

基本信息

批准号：
8784057
负责人：
Philip A. Hieter
金额：
$ 22.41万
依托单位：
UNIVERSITY OF BRITISH COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8784057
关键词：
Alleles Animal Model Applications Grants Applied Genetics Biochemical Biology Candidate Disease Gene Cataloging Catalogs Cell physiology Cells Chromosomal Instability Chromosome Segregation Chromosomes Complex DNA Damage Defect Drug Targeting Essential Genes Event Exhibits Genes Genetic Genomic Instability Goals Human Knowledge Length Malignant Neoplasms Mammalian Cell Mammals Metabolism Methodology Methods Mitotic Chromosome Modeling Molecular Mutate Mutation Organism Pathway interactions Phenotype Predisposition Principal Investigator Process RNA RNA Interference RNA Processing RNA Splicing Resources Role Saccharomycetales Signal Transduction Somatic Mutation Telomere Shortening Testing Therapeutic Work Yeasts abstracting base cancer cell cancer initiation cancer therapy chromatin immunoprecipitation genome integrity insight mRNA Cleavage and Polyadenylation Factors mutant programs protein complex research study response screening telomere transmission process tumor tumor progression tumorigenesis yeast genetics

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Mutations that cause chromosome instability (CIN) are considered important predisposing events that contribute to the initiation and/or progression of cancer. Our approach is to develop and apply genetic and biochemical methodologies to obtain an understanding of molecular components required for chromosome transmission, with the overarching goal of relating our work in yeast to human cancer. The specific aims are: 1. To characterize essential CIN genes/pathways: shortened telomere CIN genes and the ASTRA complex. We will dissect the function of the ASTRA complex and its role in telomere biology and TORC1 signaling. 2. To characterize the roles of DNA damage and RNA processing in genome integrity. Five subunits of the mRNA cleavage and polyadenylation factor (CPF) exhibit CIN and high rates of spontaneous Rad52-foci while splicing factors show wild-type levels of damage. We will characterize the mechanism by which the CPF complex and other RNA processing factors cause DNA damage and/or CIN. 3. To validate candidate somatic mutations in CIN genes involved in telomere biology and RNA metabolism, and assess sensitization of cells to knockdown of candidate synthetic lethal partners. We will evaluate methods in yeast to determine whether specific mis-sense somatic mutations found in tumors are "functional" and test synthetic lethal interactions predicted from yeast genetic interaction networks for evolutionary conservation in cultured mammalian cells. Further elucidation of the genetic basis of CIN in yeast will provide a mechanistic basis for understanding this process in human cells, and will provide candidate genes for those CIN genes mutated in cancer. Therefore, knowledge gained from this work will provide insight into tumorigensis. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述（由申请人提供）：引起染色体不稳定性（CIN）的项目摘要/抽象突变被认为是重要的诱发癌症开始和/或进展的重要事件。我们的方法是开发和应用遗传和生化方法，以了解染色体传播所需的分子成分的理解，其总体目标是将我们的酵母中的工作与人类癌症联系起来。具体目的是：1。表征必需的CIN基因/途径：缩短端粒CIN基因和Astra复合体。我们将剖析Astra复合物的功能及其在端粒生物学和TORC1信号传导中的作用。 2。表征DNA损伤和RNA处理在基因组完整性中的作用。 mRNA裂解和聚腺苷酸化因子（CPF）的五个亚基表现出CIN和较高的自发性RAD52-coci，而剪接因子显示出野生型损害水平。我们将表征CPF复合物和其他RNA处理因子引起DNA损伤和/或CIN的机制。 3。验证参与端粒生物学和RNA代谢的CIN基因中的候选体细胞突变，并评估细胞对敲低候选合成致命伴侣的敏感性。我们将评估酵母中的方法，以确定在肿瘤中发现的特定差异的体躯体突变是否是“功能性的”，并测试了从酵母遗传相互作用网络预测的合成致死相互作用，用于培养的哺乳动物细胞的进化保守性。进一步阐明酵母中CIN的遗传基础将为理解人类细胞中的这一过程提供机械基础，并将为在癌症中突变的那些CIN基因提供候选基因。因此，从这项工作中获得的知识将提供对肿瘤的见解。 PHS 398/2590（修订版06/09）页面延续格式页面