Environmental Carcinogen-DNA Adducts: NER Recognition
环境致癌物-DNA 加合物:NER 识别
基本信息
- 批准号:9275988
- 负责人:
- 金额:$ 35.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-01 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:AbateAdvanced Malignant NeoplasmAirborne Particulate MatterAromatic CompoundsBenchmarkingBindingBiological MarkersBiological MonitoringCancer EtiologyCellsCharacteristicsChemicalsComplexCrystallizationDNADNA AdductsDNA DamageDNA LibraryDNA SequenceDNA lesionDefense MechanismsDependenceDevelopmentDiseaseEnvironmentEnvironmental CarcinogensEnvironmental ExposureEnvironmental PollutantsEnvironmental PollutionEquilibriumEtiologyExposure toFoodFossil FuelsFree EnergyFundingHealthHistonesHumanHuman GenomeImpairmentIndividualInflammationInflammatory ResponseLeadLesionLibrariesMalignant - descriptorMalignant NeoplasmsMethodsMolecularMutationNucleosomesNucleotide Excision RepairOrthologous GeneOxidesPathway interactionsPharmaceutical PreparationsPoliciesPredispositionPropertyProteinsPyrimidine DimersRAD23B geneRecruitment ActivityRepair ComplexResistanceRiskRoleSignal TransductionSiteSkinStructureSunlightTestingThermodynamicsTobaccoTobacco smokeUltraviolet RaysWaterWorkXeroderma PigmentosumYeastsbasecancer preventioncarcinogenesiscarcinogenicitychemical carcinogenchemotherapeutic agentdesignexhaustexposed human populationgene repairgenotoxicityhuman diseasehuman tissueinsightnext generationnovelpublic health relevancerepairedscreeningsuperfund siteultravioletwasting
项目摘要
DESCRIPTION (provided by applicant): The human genome is under constant attack from environmental pollutants, endogenous reactive oxidizing species that are secreted in human tissues during the inflammatory response, and ultraviolet components of sunlight. Among the exogenous cancer-causing environmental contaminants are polycyclic aromatic compounds that are byproducts of fossil fuel combustion found at toxic waste dumps and superfund sites, in airborne particulates, and in our food and water. The DNA lesions derived from polycyclic aromatic compounds, inflammation-related reactive oxidizing species, and ultraviolet light result in the accumulation of malignant mutations that lead to a variety of human cancers. However, not all DNA lesions are equally effective in promoting human diseases: while lesions can be excised by the human nucleotide excision repair (NER) mechanism, some DNA lesions are rapidly repaired, some are repaired slowly, and some are entirely resistant to NER and are therefore particularly genotoxic. The vital importance of NER is demonstrated in the devastating human disorder xeroderma pigmentosum, caused by mutations in various NER genes. However, why certain DNA lesions are NER-resistant and others are not when NER is normal, is not understood. The objective of this project is to provide mechanistic insights into this puzzling variability of DNA lesion repair, by focusing on the key step of lesion recognition in NER, to yield a molecular understanding of NER resistance. We hypothesize that how well a lesion is recognized is determined by the extent of destabilization or stabilization that it impose on DNA: stabilization leads to repair resistance and destabilization facilitates repair. We will dissect the structural, dynamic and thermodynamic properties for a selected set of DNA lesions that govern whether they are recognized by Rad4-Rad23, the yeast ortholog of the human XPC-RAD23B lesion recognition factor. In Aim 1 we will determine the extent that local thermodynamic stability of lesion-containing DNA regulates their recognition. In Aim 2 we will determine the molecular mechanism for productive binding of Rad4-Rad23 that successfully recognizes the lesions and correctly recruits subsequent NER factors, and how the binding pathway and free energies along this pathway depend on lesion structures. In Aim 3 we will investigate DNA complexed with histone proteins in nucleosomes, the fundamental packaging unit of DNA in cells. We will determine how access of the NER proteins to DNA lesions in nucleosomes is governed by the lesion's structural and dynamic properties to promote or inhibit repair. The novel insights into the DNA lesion recognition mechanisms of NER that we will gain may lead to the development of more effective, less NER- susceptible chemotherapeutic agents, since the efficacy of current drugs is impaired by NER. Furthermore, such understanding will help to identify the most genotoxic cancer-causing precursors among the many environmental contaminants, thus allowing for the development of better targeted abatement policies and biomonitoring methods of the associated health risks.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Suse Broyde', 18)}}的其他基金
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
环境 DNA 损伤和诱变:损伤识别修复和聚合酶旁路的分子机制
- 批准号:
10460604 - 财政年份:2016
- 资助金额:
$ 35.66万 - 项目类别:
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
环境 DNA 损伤和诱变:损伤识别修复和聚合酶旁路的分子机制
- 批准号:
10612958 - 财政年份:2016
- 资助金额:
$ 35.66万 - 项目类别:
Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass
环境 DNA 损伤和诱变:损伤识别修复和聚合酶旁路的分子机制
- 批准号:
10293848 - 财政年份:2016
- 资助金额:
$ 35.66万 - 项目类别:
STRUCTURAL STUDY OF A DNA ADDUCT DEVIRED FROM A TUMORIGENIC METABOLITE OF BENZO
苯并致瘤代谢产物 DNA 加合物的结构研究
- 批准号:
7956119 - 财政年份:2009
- 资助金额:
$ 35.66万 - 项目类别:
STRUCTURAL STUDY OF A DNA ADDUCT DEVIRED FROM A TUMORIGENIC METABOLITE OF BENZO
苯并致瘤代谢产物 DNA 加合物的结构研究
- 批准号:
7723185 - 财政年份:2008
- 资助金额:
$ 35.66万 - 项目类别:
STRUCTURAL STUDY OF A DNA ADDUCT DEVIRED FROM A TUMORIGENIC METABOLITE OF BENZO
苯并致瘤代谢产物 DNA 加合物的结构研究
- 批准号:
7601434 - 财政年份:2007
- 资助金额:
$ 35.66万 - 项目类别:
Aromatic Amine DNA Structures--Mutagenic Relevance
芳香胺 DNA 结构--诱变相关性
- 批准号:
6522395 - 财政年份:1997
- 资助金额:
$ 35.66万 - 项目类别:
DNA Lesion Structures: Mutagenicity and Repair
DNA 损伤结构:致突变性和修复
- 批准号:
7280349 - 财政年份:1997
- 资助金额:
$ 35.66万 - 项目类别:
Aromatic Amine DNA Structures--Mutagenic Relevance
芳香胺 DNA 结构--诱变相关性
- 批准号:
6915508 - 财政年份:1997
- 资助金额:
$ 35.66万 - 项目类别:
DNA Lesion Structures: Mutagenicity and Repair
DNA 损伤结构:致突变性和修复
- 批准号:
7876627 - 财政年份:1997
- 资助金额:
$ 35.66万 - 项目类别:














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