A SIGNALING PATHWAY SPECIFIC FOR ALKYLATION DAMAGE
烷基化损伤特异的信号通路
基本信息
- 批准号:10192678
- 负责人:
- 金额:$ 36.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATR geneAlkylating AgentsAlkylating Antineoplastic AgentsAlkylationBRCA1 geneBase Excision RepairsCell physiologyCellsChemoresistanceChemosensitizationChemotherapy-Oncologic ProcedureCommon NeoplasmComplexDNADNA AlkylationDNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDNA biosynthesisDNA lesionDNA replication forkDataDefectDevelopmentDiagnosticDrug TargetingEnzymesEventGenesGenomeGenomicsGlioblastomaHumanInheritedLeadLesionLinkMalignant NeoplasmsMediatingMediator of activation proteinModalityModelingMolecularMolecular TargetMutagenesisMutateMutationNuclearOncogenicPathway interactionsPlayPoly(ADP-ribose) PolymerasesPreventionProcessPrognosisProteinsRepair ComplexResistanceResolutionRoleSignal PathwaySignal TransductionSiteSpecialized CenterSyndromeTestingTherapeuticToxic effectTransducersUbiquitinUbiquitinationWorkataxia telangiectasia mutated proteinbasecancer therapychemotherapycytotoxicgamma irradiationhelicasehuman diseaseimprovedinhibitor/antagonistinsightnovelpatient derived xenograft modelrecruitrepairedresponsescaffoldsensortumorubiquitin-protein ligase
项目摘要
Abstract
A crucial first step in DNA repair involves the recognition of genome damage, which in turn activates
signaling pathways that recruit effectors and resolve the lesion. However, whether this “sensor-
transducer-mediator” paradigm is generally applicable to pathways dedicated to repairing each
distinct type of DNA lesion remains unknown. Understanding the signaling events that mediate the
recognition and repair of DNA alkylation damage is particularly important, since alkylation
chemotherapy is one of the most widely used systemic modalities for cancer treatment. Our
preliminary studies demonstrate that human cells have a heretofore unrecognized repair signaling
pathway that is highly specific for recruiting alkylation repair factors to nuclear foci and link this
pathway to an inherited human disease. Since multiple alkylation repair factors appear to be recruited
to these foci, we have termed them nuclear SCARs (Specialized Centers for Alkylation Repair). In this
proposal, we seek to understand whether recruitment of alkylation repair factors to these sites is
critical for resolution of alkylation repair (Aim 1). We will characterize the upstream E3 ubiquitin ligase,
RNF113A, which we have found to play a central role in this pathway and is mutated in the progeroid
syndrome trichothiodystrphy (Aim 2). Finally, we will test whether targeting this pathway could
promote chemosensitization in human tumor models (Aim 3). These studies will greatly increase our
understanding of how cells detect and activate DNA repair pathways. Since alkylation repair is critical
for reversing the toxic effects of many chemotherapy agents, our work will provide new insights into
how cell respond to such therapy, and may reveal several novel molecular targets for
chemosensitization.
摘要
项目成果
期刊论文数量(0)
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NIMA MOSAMMAPARAST其他文献
NIMA MOSAMMAPARAST的其他文献
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{{ truncateString('NIMA MOSAMMAPARAST', 18)}}的其他基金
A SIGNALING PATHWAY SPECIFIC FOR ALKYLATION DAMAGE
烷基化损伤特异的信号通路
- 批准号:
10431991 - 财政年份:2018
- 资助金额:
$ 36.03万 - 项目类别:
Damaged RNA as a mediator of alkylation responses
受损的 RNA 作为烷基化反应的介质
- 批准号:
10368077 - 财政年份:2015
- 资助金额:
$ 36.03万 - 项目类别:
Damaged RNA as a mediator of alkylation responses
受损的 RNA 作为烷基化反应的介质
- 批准号:
10608048 - 财政年份:2015
- 资助金额:
$ 36.03万 - 项目类别:
MECHANISM AND REGULATION OF THE DNA ALKYLATION DAMAGE RESPONSE
DNA烷基化损伤反应的机制和调控
- 批准号:
9032479 - 财政年份:2015
- 资助金额:
$ 36.03万 - 项目类别:
MECHANISM AND REGULATION OF THE DNA ALKYLATION DAMAGE RESPONSE
DNA烷基化损伤反应的机制和调控
- 批准号:
9250732 - 财政年份:2015
- 资助金额:
$ 36.03万 - 项目类别:
Damaged RNA as a mediator of alkylation responses
受损的 RNA 作为烷基化反应的介质
- 批准号:
9974085 - 财政年份:2015
- 资助金额:
$ 36.03万 - 项目类别:
Linking histone demethylation and the DNA damage response.
将组蛋白去甲基化和 DNA 损伤反应联系起来。
- 批准号:
8321492 - 财政年份:2011
- 资助金额:
$ 36.03万 - 项目类别:
Linking histone demethylation and the DNA damage response.
将组蛋白去甲基化和 DNA 损伤反应联系起来。
- 批准号:
8508199 - 财政年份:2011
- 资助金额:
$ 36.03万 - 项目类别:
Linking histone demethylation and the DNA damage response.
将组蛋白去甲基化和 DNA 损伤反应联系起来。
- 批准号:
8091922 - 财政年份:2011
- 资助金额:
$ 36.03万 - 项目类别:
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