An organismal approach to dissecting the mechanism of DSB repair pathway choice

剖析 DSB 修复途径选择机制的有机方法

• 批准号: 8993904
• 负责人: Sarit Smolikove
• 金额: $ 27.72万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8993904
• 关键词: Accounting; Address; Affect; Alleles; Animal Model; Biochemical; Biological Assay; Biological Models; Caenorhabditis elegans; Cancer Patient; Candidate Disease Gene; Catalytic Domain; Cell Cycle Proteins; Cell Cycle Regulation; Cell Death; Cell Nucleus; Cell physiology; Cells; Cellular biology; Characteristics; Chromatin; Chromosomal translocation; Chromosome Structures; Chromosome abnormality; Complement; Complex; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Sequence Alteration; Data; Development; Diagnosis; Double Strand Break Repair; Excision; Future; Gene Expression Regulation; Gene Fusion; Gene Structure; Genes; Genetic; Genetic Epistasis; Genetic Screening; Genome; Genomic Instability; Goals; Human; Lead; Life; Malignant Neoplasms; Mammals; Measures; Meiosis; Methods; Modeling; Molecular; Molecular Genetics; Molecular Mechanisms of Action; Morbidity - disease rate; Nonhomologous DNA End Joining; Organism; Outcome; Participant; Pathway interactions; Pharmaceutical Preparations; Play; Prevention; Process; Property; Proteins; Public Health; RNA interference screen; Radiation therapy; Reagent; Regulation; Replication Error; Research; Role; Single-Stranded DNA; System; Testing; Time; Translational Research; V(D)J Recombination; Whole Organism; Yeasts; base; cancer cell; cancer therapy; chromatin modification; cost; design; ds-DNA; gene conservation; gene discovery; gene repair; genome integrity; homologous recombination; improved; insertion/deletion mutation; insight; mutant; novel; prevent; programs; protein complex; public health relevance; repaired; therapy design; tumor; tumor progression; yeast two hybrid system

DESCRIPTION (provided by applicant): Project Summary A double stand break is a type of DNA damage which involves the severing of one DNA molecule into two parts. Unrepaired breaks are harmful to living organisms since they lead to cell death. However, cells that do repair their breaks can also suffer detrimental outcomes if the repair is associated with DNA alteration. Repair pathways can be error free, restoring the DNA to its pristine condition, or error-prone, leading to mistakes in DNA repair. The latter may lead to chromosomal abnormalities frequently associated with changes in gene structure and regulation. The effects of these errors on chromosome structure and gene regulation often promote tumors and are frequently found in cells of cancer patient. A low level of DNA breaks occur due to normal cellular process and some are environmentally induced (for example, radiation therapy and/or chemotherapeutic drugs). If this damage is not properly repaired, it can contribute to cancer reoccurrence. Understanding processes involved in how a particular DNA repair mechanism is selected will be fundamental for determining how cancer progresses as well as for cancer treatment. The long-term goal of this research is to identify mechanisms involved in selecting an error-free repair vs. an error-prone repair pathway. This proposal focuses on identifying proteins and mechanisms involved in this choice. Studies are proposed to understand how processing of double stand break affects such a decision. We will use C. elegans, a multi- cellular animal model system which allows us to preform genetic assays for DNA repair in whole organism, at a low cost and with efficient time scale. Using a newly identified mutant in a key repair gene, we will examine DNA processing independently of DNA damage in the C. elegans germline. Furthermore, we will identify new mechanisms directly regulating a key protein involved in this processing. To complement this analysis, we will study the germline as a model for the cell-cycle control of DNA processing by designing a system for targeting DNA damage to particular regions of the germline. The conservation of genes and pathways between this animal model and humans will serve as efficient approach for discovery of genes in humans affecting the formation and progression of cancer. Understanding how accurate versus error-prone pathways are selected will be essential for developing anti-cancer therapies utilizing DNA damage to destroy cancer cells without harming healthy non-cancerous cells.

描述（由申请人提供）：