Regulation of Replication Checkpoint by Proteolysis
蛋白水解调节复制检查点
基本信息
- 批准号:7483524
- 负责人:
- 金额:$ 21.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-06-25 至 2009-04-30
- 项目状态:已结题
- 来源:
- 关键词:AneuploidyBindingBiochemical GeneticsCDC6 geneCDT1 GeneCell CycleCell Cycle CheckpointCell Cycle RegulationCell NucleusCell divisionCellsChromatinComplexConditionCyclin ACyclin-Dependent KinasesDNA DamageDNA Replication FactorDNA biosynthesisDNA damage checkpointDrosophila genusEnsureFaceFamilyG2 PhaseGemininGene AmplificationGenomeGenome StabilityGenomicsHumanIn VitroLicensing FactorMaintenanceMalignant NeoplasmsMammalian CellMediatingMedical SurveillanceMitosisMitoticMolecularNormal CellPathway interactionsPhasePloidiesPolyploid CellsPolyploidyPre-Replication ComplexProcessProliferatingProteinsProteolysisRadiationRegulationReplication InitiationReplication LicensingReplication OriginSignal TransductionUbiquitinXenopusYeastsbasecancer cellchromosome replicationhelicasehuman CDC6 proteininhibitor/antagonistinsightirradiationnovelorigin recognition complexpreventreconstitutionresponsetumorigenesisubiquitin-protein ligaseultraviolet irradiation
项目摘要
DESCRIPTION (provided by applicant): The broad and long term objectives of this proposal are to elucidate the molecular mechanisms that regulate genome stability in the cell cycle. Alteration of genome stability is a hallmark of human cancer. Cancer is often associated with polyploidy, aneuploidy and gene amplification. These genomic alterations allow cancer cells to proliferate under conditions that normal cells cannot. Recent studies suggest that replication is precisely regulated by the cell cycle to occur only once per cell cycle. Many lines of evidence indicate that replication licensing is critical for the control of re-replication and therefore genome reduplicatoin. In the cell cycle, the pre-replication complex (Pre-RC) assembles onto the replication origins at the end of mitosis and during G1 to potentiate chromatin duplication in S phase. The initial step for Pre-Rc assembly is the binding of the origin recognition complex (ORC) to the origins. CDC6 and CDT1 then associate with ORC to promote the loading of the MCM2-7 proteins. We have previously found that loss of either cyclin A or geminin, a replication inhibitor that binds to the replication licensing factor CDT1, induces accumulation of polyploid cells containing DNA content between 4N and 8N. In this application, we propose to investigate our new finding that CDT1 serves as a direct checkpoint target in response to DNA damage. We found that CDT1 is proteolyzed within minutes in response to gamma-irradiation. We have provided genetic and biochemical evidence indicating this checkpoint control represents a new checkpoint pathway independent of ATM/CHK2 and replication. We also present evidence for the involvement of an uncharacterized ubiquitin E3 ligase complex that targets CDT1 for ubiquitin-dependent degradation. We propose to investigate this new checkpoint. Our specific aims are: 1) To determine the signal that causes CDT1 degradation in response to DNA damage. 2) To isolate the new E3 ligase complex. 3) To recapitulate the CDT1 degradation in vitro. 4) To examine the cell cycle regulation of CDT1 by ubiquitin-dependent proteolysis. Since CDT1 is a critical regulator for replication licensing, understanding of its regulation should provide novel insight into the mechanism for genome stability.
描述(由申请人提供):本提案的广泛和长期目标是阐明调节细胞周期中基因组稳定性的分子机制。基因组稳定性的改变是人类癌症的标志。癌症通常与多倍体、非整倍体和基因扩增有关。这些基因组改变使癌细胞能够在正常细胞不能的条件下增殖。最近的研究表明,复制是由细胞周期精确调节,每个细胞周期只发生一次。许多证据表明,复制许可对于控制再复制和基因组复制至关重要。在细胞周期中,复制前复合物(Pre-RC)在有丝分裂结束时和G1期组装到复制起点上,以加强S期的染色质复制。Pre-Rc组装的初始步骤是起始点识别复合物(ORC)与起始点的结合。然后,CDC 6和CDT 1与ORC结合以促进MCM 2 -7蛋白的负载。我们以前已经发现,细胞周期蛋白A或双生蛋白,复制抑制剂,结合到复制许可因子CDT 1的损失,诱导的多倍体细胞的DNA含量在4 N和8 N之间的积累。在这个应用中,我们建议调查我们的新发现,CDT 1作为一个直接的检查点目标,在响应DNA损伤。我们发现,CDT 1是在几分钟内响应于γ-辐射的蛋白水解。我们提供的遗传和生化证据表明,这种检查点控制代表了一种新的检查点途径,独立于ATM/CHK 2和复制。我们还提供了证据表明,一种未表征的泛蛋白E3连接酶复合物参与其中,该复合物靶向CDT 1进行泛蛋白依赖性降解。我们建议调查这个新的检查站。我们的具体目标是:1)确定响应DNA损伤导致CDT 1降解的信号。2)分离新的E3连接酶复合物。3)概括CDT 1在体外的降解。4)研究CDT 1通过泛素依赖性蛋白水解对细胞周期的调控。由于CDT 1是复制许可的关键调节器,因此对其调节的理解应该为基因组稳定性机制提供新的见解。
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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HUI ZHANG其他文献
HUI ZHANG的其他文献
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蛋白水解调节复制检查点
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