Etiology of Chromosome Translocations

染色体易位的病因学

基本信息

批准号：
7877976
负责人：
SANG EUN LEE
金额：
$ 23.52万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7877976
关键词：
Biochemical Biochemistry Biological Assay Biological Models Blood typing procedure Cell Cycle Checkpoint Cells Cellular biology Childhood Chromosomal Breaks Chromosomal translocation Chromosome abnormality Chromosomes Complex DNA DNA Damage DNA Double Strand Break DNA lesion Defect Detection Diagnosis Disease Double Strand Break Repair Etiology Fluorescence Microscopy Frequencies Gene Mutation Genes Genetic Genetic Screening Genome Goals Hematopoietic Neoplasms Hereditary Disease Human Kinetics Light Malignant Childhood Neoplasm Malignant lymphoid neoplasm Mediating Modeling Molecular Monitor Nonhomologous DNA End Joining Oncogenic Pathway interactions Patients Phosphorylation Population Preventive Process Proteins Reaction Reciprocal Translocation Research Role Saccharomyces cerevisiae Sequence Analysis Signal Transduction Site System Techniques Therapeutic Time Treatment Protocols Yeasts base cancer type carcinogenesis cohesin genetic analysis in vivo insight mutant novel outcome forecast prevent programs public health relevance repaired response sarcoma time use

项目摘要

DESCRIPTION (provided by applicant): Chromosome translocations are frequently associated with many types of blood cancers and childhood sarcomas. Clinically, chromosome translocations are important because they offer the ability to precisely diagnose the type of cancers and to tailor treatment. Paradoxically, the molecular mechanism that leads to chromosome translocations is not well understood. The available evidence suggests the role of process repairing DNA double strand breaks in the formation of chromosome translocations. Recently, we developed a novel yeast-based model system to detect non-homologous end joining (NHEJ)- dependent, reciprocal chromosome translocations in vivo. This system allowed us to detect in real time a reciprocal translocation of site-specific DNA double strand breaks from a population of cells. A screen using our system resulted in the identification of several gene mutations that elevate the frequency of NHEJ- dependent chromosome translocations. Through this system, we uncovered a role of a specific DNA damage surveillance pathway in suppression of chromosome translocations. The focus of this proposal is to identify and characterize the genetic network that suppresses chromosome translocation. An approach combining genetics, cell biology and biochemistry will be used to provide mechanistic insights into genetic and mechanistic underpinnings of NHEJ-mediated chromosome translocations. These studies will shed light on the molecular mechanism leading to chromosome translocations in humans and may provide conceptual basis for advanced therapeutics to treat or prevent blood cancers. PUBLIC HEALTH RELEVANCE: The long-term objective of our research program is to dissect the molecular mechanism that causes oncogenic chromosome translocations. Mutations of genes identified by our study are known to enforce one of the DNA damage surveillance pathways, which can suppress chromosome translocations, and predispose patients to chromosomal translocations and lymphoid malignancy. This application will identify and characterize damage- surveillance and other mechanisms that suppress chromosome translocation to understand the defects in blood cancers and develop novel preventive and/or therapeutic strategies.

描述（由申请人提供）：染色体易位经常与许多类型的血液癌和儿童肉瘤有关。在临床上，染色体易位很重要，因为它们具有精确诊断癌症类型和量身定制治疗的能力。矛盾的是，导致染色体易位的分子机制尚不清楚。现有证据表明，修复DNA双链断裂的过程在染色体易位形成中的作用。最近，我们开发了一种基于酵母菌的新型模型系统，以检测非同源末端连接（NHEJ） - 依赖性的，相互的染色体易位。该系统允许我们实时检测到位点特异性DNA双链从一群细胞群中断裂的相互易位。使用我们的系统的屏幕导致鉴定了几种基因突变，这些基因突变升高了依赖NHEJ依赖性染色体易位的频率。通过该系统，我们发现了特定的DNA损伤监视途径在抑制染色体易位中的作用。该建议的重点是识别和表征抑制染色体易位的遗传网络。结合遗传学，细胞生物学和生物化学的方法将用于提供机械洞察，以了解NHEJ介导的染色体易位的遗传和机械基础。这些研究将阐明导致人类染色体易位的分子机制，并可能为晚期治疗或预防血液癌的晚期治疗提供概念基础。公共卫生相关性：我们的研究计划的长期目标是剖析导致致癌染色体易位的分子机制。已知通过我们的研究鉴定的基因突变可以强制执行一种DNA损伤监测途径之一，该途径可以抑制染色体易位，并使患者容易受到染色体易位和淋巴性恶性肿瘤的影响。该应用将确定并表征损害监测和其他抑制染色体易位的机制，以了解血液癌的缺陷并发展新颖的预防性和/或治疗策略。