DNA repair pathways preserve cellular homeostasis
DNA 修复途径维持细胞稳态
基本信息
- 批准号:10046506
- 负责人:
- 金额:$ 44.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATR geneAerobicAgingAnaerobic BacteriaAntioxidantsBase Excision RepairsCell AgingCell CycleCell Cycle CheckpointCellsCellular MorphologyCellular Stress ResponseCharacteristicsChemicalsCytological TechniquesDNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDNA biosynthesisDNA damage checkpointDNA lesionDNA replication forkDNA strand breakDefectDependenceEnzymesEukaryotaEukaryotic CellExcisionExhibitsFree RadicalsG2 PhaseGenerationsGenesGeneticGenetic EpistasisGenetic TechniquesGenomeGrowthHomeostasisHumanImpairmentIndividualLeadLesionLibrariesMalignant NeoplasmsMeasuresMicroscopyModelingMonitorMorphologyPathway AnalysisPathway interactionsPhasePhenotypePhosphorylationPhysiologicalPhysiologyPlayPloidiesPopulationPropertyProteinsPulsed-Field Gel ElectrophoresisRAD52 geneRad30 proteinRadiationReactive Oxygen SpeciesResearchRiskRoleSS DNA BPSaccharomyces cerevisiaeSaccharomycetalesSeriesSignal TransductionSingle-Stranded DNASourceSystemTailTechniquesTestingTimeWorkYeastsbasecarcinogenesisexperimental studygenome integrityhomologous recombinationhuman diseasemutantnucleaseoverexpressionphysical propertypreservationpreventrepairedresponse
项目摘要
Project Summary
Eukaryotic cells employ several major DNA repair pathways to monitor and maintain the
integrity of their genomes. Most past research has focused on characterization of the
fundamental mechanisms and key proteins involved in these pathways after exposure of cells to
exogenous chemicals or radiation. By contrast, the roles played by these repair systems in
responding to the tens of thousands of DNA lesions that form spontaneously within cells each
day is largely unexplored. In this proposed study, which we believe is the first of its kind, we will
investigate the roles of all major pathways in maintaining cellular homeostasis during normal
growth, i.e., in response to endogenous rather than exogenous sources of DNA damage. Our
preliminary studies revealed that Saccharomyces cerevisiae (budding yeast) mutants defective in
repair of DNA double-strand breaks (DSBs) by the homologous recombination (HR) pathway
exhibit many phenotypes caused by unrepaired lesions. These phenotypes include a 3-fold
increase in time spent in G2 phase, a characteristic dependent on the presence of functional
DNA damage checkpoint genes, as well as strongly increased G2 DNA content revealed by
FACS analysis, greatly enlarged cells, and striking changes in other morphological and physical
properties. We subsequently screened mutants from a yeast deletion strain library to ask what
other major repair pathways are most critical during normal growth. Mutants of only one other
pathway, base excision repair (BER), also exhibited strong cellular stress responses. We
propose to perform a series of experiments that will expand upon these findings by (1)
characterizing the persistently activated DNA damage response in HR mutants using genetic and
microscopy-based techniques, (2) performing critical tests of a model for persistent checkpoint
activation in HR mutants, (3) characterizing the constitutive DNA damage signaling response in
BER pathway mutants, and (4) performing experiments that will critically test the roles of reactive
oxygen species (ROS) and stalled replication forks in generation of endogenous checkpoint-
activating DNA lesions. Our major hypothesis is that defects in HR and BER, but not other
pathways, lead to high levels of unrepaired lesions that stimulate a recurring checkpoint signaling
cascade and many quantifiable physiological changes in cells. Since the major DNA repair
pathways analyzed in this project are conserved in all eukaryotes including humans, the findings
of the work will have strong relevance to the related fields of human carcinogenesis and cellular
aging.
项目摘要
真核细胞采用几种主要的DNA修复途径来监视和维护
其基因组的完整性。过去的大多数研究都集中在表征
细胞暴露于这些途径的基本机制和关键蛋白
外源化学物质或辐射。相比之下,这些维修系统在
响应成千上万的DNA病变,它们在每个细胞内自发形成
一天在很大程度上没有探索。在这项拟议的研究中,我们认为这是同类的第一个研究,我们将
研究正常情况下所有主要途径在维持细胞稳态方面的作用
生长,即响应内源性而不是外源性DNA损伤来源。我们的
初步研究表明,酿酒酵母(发芽酵母)突变体有缺陷
通过同源重组(HR)途径修复DNA双链断裂(DSB)
表现出由未修复的病变引起的许多表型。这些表型包括3倍
在G2阶段所花费的时间增加,这是依赖于功能的特征
DNA损伤检查点基因,以及强烈增加的G2 DNA含量
FACS分析,大大扩大细胞,以及其他形态和物理的引人注目的变化
特性。随后,我们从酵母缺失菌株库中筛选突变体,以询问什么
在正常生长期间,其他主要的维修途径最为关键。彼此的突变体
途径,基础切除修复(BER)也表现出强烈的细胞应力反应。我们
提议执行一系列实验,这些实验将通过(1)扩展到这些发现上
使用遗传和
基于显微镜的技术,(2)对持续检查点的模型进行关键测试
(3)在HR突变体中的激活,表征本构中DNA损伤信号响应
BER途径突变体和(4)执行实验,这些实验将批判性地测试反应性的作用
氧(ROS)和倒闭的复制叉在产生内源检查点 -
激活DNA病变。我们的主要假设是人力资源和BER的缺陷,但没有其他假设
途径,导致高水平的未修复病变刺激重复的检查点信号传导
级联细胞中的级联和许多可量化的生理变化。由于主要的DNA修复
该项目中分析的途径在包括人类在内的所有真核生物中都保存
这项工作将与人类致癌和细胞的相关领域有很强的相关性
老化。
项目成果
期刊论文数量(0)
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专利数量(0)
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Lysle Kevin Lewis其他文献
Lysle Kevin Lewis的其他文献
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{{ truncateString('Lysle Kevin Lewis', 18)}}的其他基金
Genome-wide analysis identifies genes required for repair of DNA strand breaks
全基因组分析识别修复 DNA 链断裂所需的基因
- 批准号:
8289252 - 财政年份:2012
- 资助金额:
$ 44.03万 - 项目类别:
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