ATM activation by DNA single-strand breaks
DNA 单链断裂激活 ATM
基本信息
- 批准号:10193366
- 负责人:
- 金额:$ 18.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-17 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:APEXL2 GeneATM activationBiochemicalCancer EtiologyCell Cycle ProgressionComplexDNA DamageDNA Double Strand BreakDNA RepairDNA Single Strand BreakDNA lesionDataDiseaseDouble Strand Break RepairEnvironmental ExposureEnzymesExcisionExonucleaseGenome StabilityIn VitroMalignant NeoplasmsMammalian CellMediatingMolecularMutagenesisNeurodegenerative DisordersNucleic AcidsOxidative StressPathologyPathway interactionsPharmaceutical PreparationsPlasmidsPlayProteinsPublishingRanaResearchResourcesRoleSeriesSignal TransductionSingle Strand Break RepairSiteStructureSystemTestingTopoisomeraseToxic Environmental SubstancesUnited States National Institutes of HealthXenopusbasecancer therapychemotherapyeggendonucleasegenome integrityinsertion/deletion mutationnovelnucleasepreservationreconstitutionrecruitrepairedresponse
项目摘要
Project Summary/Abstract
As the most common form of DNA lesions, DNA single-strand breaks (SSBs) are derived from
environmental toxins and chemotherapy drugs as well as endogenous resources such as intermediate
DNA repair products in oxidative stress, and have been implicated in association with cancer and
neurodegenerative disorders. Whereas it is widely accepted that ATM is essential for the repair and
signaling of DNA double-strand breaks (DSBs), it remains unknown whether and how SSBs trigger ATM
activation, and how SSB-induced ATM activation maintains genome stability at the molecular level. Our
substantial preliminary data using biochemical, structure and function analyses suggest that ATM-
mediated DNA damage response (DDR) pathway is activated by the defined SSB structure in Xenopus
egg extracts and that such SSB-induced ATM activation is earlier than ATR activation. Notably, further
mechanistic studies suggest that a critical upstream regulator is implicated in the SSB-induced ATM
activation. Thus, we will dissect the molecular mechanisms of SSB-induced ATM activation in genome
integrity via two Specific Aims: (1) determine whether and how ATM-mediated DDR pathway is activated
by defined SSB structures in Xenopus egg extracts and reconstitution system with purified proteins, and
(2) determine the mechanism of how this upstream regulator contributes to the SSB-induced ATM
activation. Anticipated results from this NIH R21 project will provide direct evidence that ATM is activated
by defined SSB structures and how SSB-induced ATM activation is regulated and coordinated. Thus, our
studies will provide novel avenues for potential cancer therapies through the modulation of distinct
regulatory mechanisms of SSB-induced ATM activation in genome integrity and cancer etiology.
项目总结/摘要
作为最常见的DNA损伤形式,DNA单链断裂(SSB)来源于
环境毒素和化疗药物以及内源性资源,如中间体
氧化应激中的DNA修复产物,并与癌症和
神经退行性疾病尽管人们普遍认为ATM对于修复和维护是必不可少的,
DNA双链断裂(DSB)的信号,它仍然是未知的SSBs是否以及如何触发ATM
激活,以及SSB诱导的ATM激活如何在分子水平上维持基因组稳定性。我们
利用生化、结构和功能分析的大量初步数据表明,ATM-
介导的DNA损伤反应(DDR)途径被非洲爪蟾中定义的SSB结构激活
卵提取物,并且这种SSB诱导的ATM激活早于ATR激活。值得注意的是,
机制研究表明,一个关键的上游调节因子与SSB诱导的ATM有关,
activation.因此,我们将在基因组中剖析SSB诱导ATM激活的分子机制
通过两个特定目的实现完整性:(1)确定ATM介导的DDR通路是否以及如何被激活
通过在爪蟾卵提取物中确定的SSB结构和用纯化蛋白质重建系统,和
(2)确定该上游调节剂如何促进SSB诱导的ATM的机制
activation. NIH R21项目的预期结果将提供ATM被激活的直接证据
通过定义的SSB结构以及SSB诱导的ATM激活如何调节和协调。所以我们
研究将通过调节不同的细胞因子,
SSB诱导的ATM激活在基因组完整性和癌症病因学中的调节机制。
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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Shan Yan其他文献
Shan Yan的其他文献
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{{ truncateString('Shan Yan', 18)}}的其他基金
Role of TopBP1 partner WDR18 in DNA damage checkpoint and DNA replication
TopBP1 伴侣 WDR18 在 DNA 损伤检查点和 DNA 复制中的作用
- 批准号:
8290653 - 财政年份:2012
- 资助金额:
$ 18.88万 - 项目类别:
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MRN 复合物和 DNA 双链断裂激活 ATM 的机制
- 批准号:
9911787 - 财政年份:2020
- 资助金额:
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ATM Activation and its functional Importance in DNA damage response
ATM 激活及其在 DNA 损伤反应中的功能重要性
- 批准号:
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- 资助金额:
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