Functions of SRAP domain proteins in DNA metabolism
SRAP结构域蛋白在DNA代谢中的功能
基本信息
- 批准号:9751009
- 负责人:
- 金额:$ 43.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AgingAgrochemicalsAir PollutionAlkylating AgentsAlkylationBacteriaBindingBiochemicalBiochemical GeneticsBypassCarbonCellsChemicalsChloroformClinicalCoupledCysteineCytosineDNADNA BindingDNA DamageDNA RepairDNA Repair GeneDNA Repair PathwayDNA biosynthesisDNA lesionDNA replication forkDNA-Directed DNA PolymeraseDNA-protein crosslinkDataDetergentsDietDiseaseEnvironmental ExposureEnzymatic BiochemistryEpigenetic ProcessExposure toFailureFoodFrequenciesFutureGene ExpressionGenesGeneticGenetic ScreeningGenetic StructuresGenomeGenome StabilityGenotoxic StressGuanineHumanHydroxyl RadicalHypersensitivityIonizing radiationKnock-outLesionLifeLigandsLinkMaintenanceMalignant NeoplasmsMetabolismMethodsModelingMutagenesisMutagensMutationN-terminalNitrosaminesOrganismOxidantsOxidative StressOxidesPathway interactionsPeptide HydrolasesPhenotypePlasticsPolymeraseProcessProteinsProteomicsRadiationReportingResolutionS PhaseSOS ResponseSS DNA BPSaccharomyces cerevisiaeSingle-Stranded DNASiteSolventsSourceStructureSystemTertiary Protein StructureTestingTherapeutic InterventionToxic Environmental SubstancesUV Radiation ExposureYeastsadductbaseblastomere structurecrosslinkendonucleaseenvironmental toxicologyexperimental studyfitnessgenetic approachgenome integrityinnovationloss of functionnucleaseoxidationpotassium bromatepreventprotein crosslinkprotein functionrecruitrepair enzymerepairedresponsesuicide enzymetargeted treatment
项目摘要
PROJECT SUMMARY
Thousands of abasic sites form daily in each of our cells. Many types of environmental toxins that cause
alkylation or oxidation of DNA bases to form N7-guanine adducts and 8-oxoguanine induce abasic sites.
For example, N-nitrosamines that are found in foods, detergents, solvents, plastics, and agricultural
chemicals as well as chemicals like carbon tetracholoride, potassium bromate, and chloroform that induce
oxidative stress all increase the frequency of abasic sites in DNA. Failures in managing this ubiquitous
form of DNA damage can cause a variety of diseases including cancer. The known mechanisms of repair
require an intact DNA duplex; however, abasic sites form more readily in single-stranded DNA where they
are impediments to replicative polymerases. We utilized unbiased proteomic and genetic approaches to
understand how replication forks deal with challenges to genotoxic stresses with the premise that
uncharacterized proteins identified in both approaches would be strong candidates for new DNA damage
response proteins. Both the proteomic and genetic screens identified HMCES (hydroxyl-methyl cytosine
embryonic cell specific) as a candidate genome maintenance protein functioning at replication forks.
HMCES was reported to bind and remove 5-hydroxymethyl cytosine from DNA and thereby regulate gene
expression. Our preliminary data suggests that HMCES independently functions as a replication-
associated DNA repair protein. HMCES contains an evolutionarily ancient domain (SRAP). We
hypothesize that SRAP proteins provide a mechanism to repair or tolerate DNA damage during DNA
replication. This proposal will utilize biochemical, genetic, and structural approaches in human, yeast, and
bacterial systems to determine how SRAP proteins maintain genome stability. Completing these studies
will generate paradigm setting discoveries within the fields of environmental toxicology, DNA repair, DNA
replication, epigenetic control, and enzymology.
项目概要
我们的每个细胞中每天都会形成数以千计的脱碱基位点。许多类型的环境毒素会导致
DNA碱基的烷基化或氧化形成N7-鸟嘌呤加合物和8-氧代鸟嘌呤诱导脱碱基位点。
例如,食品、洗涤剂、溶剂、塑料和农业产品中存在的 N-亚硝胺
化学物质以及四氯化碳、溴酸钾和氯仿等化学物质
氧化应激都会增加 DNA 中脱碱基位点的频率。管理这种无处不在的失败
DNA损伤可能导致多种疾病,包括癌症。已知的修复机制
需要完整的 DNA 双链体;然而,无碱基位点在单链 DNA 中更容易形成,
是复制聚合酶的障碍。我们利用公正的蛋白质组学和遗传学方法
了解复制叉如何应对基因毒性应激的挑战,前提是
两种方法中鉴定出的未表征的蛋白质将是新 DNA 损伤的有力候选者
反应蛋白。蛋白质组和遗传筛选均鉴定出 HMCES(羟甲基胞嘧啶)
胚胎细胞特异性)作为在复制叉上发挥作用的候选基因组维持蛋白。
据报道,HMCES 可以结合并去除 DNA 中的 5-羟甲基胞嘧啶,从而调节基因
表达。我们的初步数据表明 HMCES 独立发挥复制功能
相关DNA修复蛋白。 HMCES 包含一个进化古老的域(SRAP)。我们
假设 SRAP 蛋白提供了一种修复或耐受 DNA 损伤过程中的 DNA 损伤的机制
复制。该提案将利用生物化学、遗传和结构方法研究人类、酵母和
细菌系统来确定 SRAP 蛋白如何维持基因组稳定性。完成这些研究
将在环境毒理学、DNA 修复、DNA 领域产生范式设定发现
复制、表观遗传控制和酶学。
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('David K Cortez', 18)}}的其他基金
Functions of SRAP domain proteins in DNA metabolism
SRAP结构域蛋白在DNA代谢中的功能
- 批准号:
9901531 - 财政年份:2019
- 资助金额:
$ 43.76万 - 项目类别:
Functions of SRAP domain proteins in DNA metabolism
SRAP结构域蛋白在DNA代谢中的功能
- 批准号:
10318157 - 财政年份:2019
- 资助金额:
$ 43.76万 - 项目类别:
Functions of SRAP domain proteins in DNA metabolism
SRAP结构域蛋白在DNA代谢中的功能
- 批准号:
10541820 - 财政年份:2019
- 资助金额:
$ 43.76万 - 项目类别:
2017 Mammalian DNA Repair Gordon Research Conference & Gordon Research Seminar
2017年哺乳动物DNA修复戈登研究会议
- 批准号:
9261069 - 财政年份:2017
- 资助金额:
$ 43.76万 - 项目类别:
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Functions of SRAP domain proteins in DNA metabolism
SRAP结构域蛋白在DNA代谢中的功能
- 批准号:
9901531 - 财政年份:2019
- 资助金额:
$ 43.76万 - 项目类别:
Functions of SRAP domain proteins in DNA metabolism
SRAP结构域蛋白在DNA代谢中的功能
- 批准号:
10318157 - 财政年份:2019
- 资助金额:
$ 43.76万 - 项目类别:
Functions of SRAP domain proteins in DNA metabolism
SRAP结构域蛋白在DNA代谢中的功能
- 批准号:
10541820 - 财政年份:2019
- 资助金额:
$ 43.76万 - 项目类别: