Mismatch Repair Interactions
错配修复相互作用
基本信息
- 批准号:8555257
- 负责人:
- 金额:$ 31.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-09-27 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAddressAffinityBase PairingBiochemical GeneticsCellsCellular biologyCharacteristicsCollaborationsComplexDNADNA DamageDNA Double Strand BreakDNA RepairDNA lesionDNA-Protein InteractionDefectDeuteriumEquilibriumEscherichia coliEventExcisionExodeoxyribonuclease IGeneticGenetic RecombinationGoalsHumanHuman CharacteristicsImmunoglobulin GenesImmunoglobulin Somatic HypermutationIn VitroInheritedLesionLigandsLinkMLH1 geneMSH2 geneMSH6 geneMalignant NeoplasmsMapsMass Spectrum AnalysisMethodsMismatch RepairMolecular BiologyMolecular ConformationMutationNatureNeurodegenerative DisordersPMS1 genePMS2 genePathway interactionsPeptidesPhasePlayPredispositionPreparationProcessProductionPropertyProtein RegionProteinsRegimenResistanceRoentgen RaysRoleSaccharomyces cerevisiaeScreening procedureSequence HomologsSet proteinSignal TransductionSite-Directed MutagenesisStructureSystemSystems AnalysisTherapeuticTrinucleotide RepeatsVariantYeastsantitumor drugcancer therapyconformational conversioncytotoxicendonucleasehelicasehomologous recombinationin vivoinhibitor/antagonistinsightmutantneoplastic cellpreventprotein protein interactionrepairedresponsesmall moleculetherapy development
项目摘要
DNA mismatch repair is a major contributor to genetic stability. Mismatch repair defects confer strong cancer predisposition and have implications for cancer therapy because inactivation of the pathway renders cells resistant to the cytotoxic effects of certain anti-tumor drugs, a consequence of participation of the system in the DNA damage response. Perhaps surprisingly, mismatch repair function is also required for production of certain mutations, such as the expansion of (CAG){n} repeat sequences, the primary cause of a number of neurodegenerative diseases. The goals of this project to clarify conformations, conformational variation, and structures of multi-protein, protein-DNA, and multi-protein DNA assemblies that are key intermediates in DNA lesion processing and damage signaling by the mismatch repair system. Our aims are 3-fold: (1) Using deuterium exchange mass spectrometry (DXMS), we have identified regions of bacterial MutS and eukaryotic MutS-alpha (MSH2-MSH6) that undergo substrate-dependent conformational transitions. These regions will be subjected to site-directed mutagenesis and the resulting mutants characterized for their impact on mismatch repair both in vivo and in vitro. (2) Small angle X-ray scattering, equilibrium methods, DXMS, x-ray crystallographic, biochemical and genetic approaches as appropriate will be utilized to extend our understanding of multi-protein assemblies involved in mismatch repair. These assemblies will include PCNA complexes with MutS-alpha (MSH2-MSH6) and MutL-alpha (MLH1-PMS1/PMS2), MutSa complexes with exonuclease 1 and with Chk1, and the complex between exonuclease 1 and the BLM helicase. The latter study will be pursued in collaboration with Project 4. (3) Human MutS-alpha and MutS-Beta differ in the manner in which they interact with PCNA and MutL-alpha, indicating that MutS-alpha- and MutS-Beta-triggered repair events proceed by significantly different mechanisms. In view of the known involvement of MutS-Beta and MutL-alpha in the somatic phase (CAG){n}:(CTG){n}, triplet repeat expansion, we will seek small molecule inhibitors that specifically block MutS Beta-triggered repair events by screening for compounds that selectively block assembly the MutL-alpha-MutS-Beta-DNA ternary complex.
DNA错配修复是遗传稳定性的主要贡献者。错配修复缺陷赋予强烈的癌症易感性,并对癌症治疗有影响,因为该途径的失活使细胞对某些抗肿瘤药物的细胞毒性作用具有抗性,这是该系统参与DNA损伤反应的结果。也许令人惊讶的是,某些突变的产生也需要错配修复功能,例如(CAG){n}重复序列的扩展,这是许多神经退行性疾病的主要原因。本项目的目标是阐明多蛋白质、蛋白质-DNA和多蛋白质DNA组装体的构象、构象变异和结构,这些组装体是错配修复系统进行DNA损伤处理和损伤信号传导的关键中间体。我们的目标有三个方面:(1)使用氘交换质谱(DXMS),我们已经鉴定了细菌MutS和真核MutS-α(MSH 2-MSH 6)的经历底物依赖性构象转变的区域。将对这些区域进行定点诱变,并对所得突变体进行体内和体外对错配修复的影响的表征。(2)小角X射线散射,平衡方法,DXMS,X射线晶体学,生物化学和遗传学的方法,适当的将被用来扩展我们的理解,多蛋白组装参与错配修复。这些组装体将包括PCNA与MutS-α(MSH 2-MSH 6)和MutL-α(MLH 1-PMS 1/PMS 2)的复合物,MutSa与核酸外切酶1和Chk 1的复合物,以及核酸外切酶1和BLM解旋酶之间的复合物。后一项研究将与项目4合作进行。(3)人类MutS-α和MutS-β与PCNA和MutL-α相互作用的方式不同,表明MutS-α和MutS-β触发的修复事件通过显著不同的机制进行。鉴于已知MutS-β和MutL-α参与体细胞期(CAG){n}:(CTG){n}三联体重复扩增,我们将通过筛选选择性阻断MutL-α-MutS-β-DNA三元复合物组装的化合物来寻求特异性阻断MutS β触发的修复事件的小分子抑制剂。
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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PAUL LAWRENCE MODRICH其他文献
PAUL LAWRENCE MODRICH的其他文献
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{{ truncateString('PAUL LAWRENCE MODRICH', 18)}}的其他基金
Nucleic Acids 2008 Gordon Research Conference
核酸 2008 年戈登研究会议
- 批准号:
7477373 - 财政年份:2008
- 资助金额:
$ 31.57万 - 项目类别:
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