Regulation of polymerase switching in translesion synthesis
跨损伤合成中聚合酶转换的调节
基本信息
- 批准号:8972006
- 负责人:
- 金额:$ 32.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:Base PairingBindingBypassCatalytic DomainCell CycleCellsComplexDataDefectDeubiquitinating EnzymeDeubiquitinationEmbryoEnvironmental Risk FactorEventFibroblastsFrequenciesGenesGeneticGenomeGenome StabilityGenomic InstabilityGenotoxic StressGoalsHumanKnock-outLesionLightMaintenanceMalignant NeoplasmsMetabolismMetalloproteasesMusMutagenesisMutationNucleotidesPhysiologicalPlayPolymerasePreventionProcessProteinsRecruitment ActivityRegulationRoleSiteSlideTestingTumor SuppressionUV inducedUbiquitinUbiquitinationZincdimerds-DNAin vitro activityin vivoinsightinterestmouse modelnovelpreventpublic health relevancerepairedthree-dimensional modelingtumor
项目摘要
DESCRIPTION (provided by applicant): Environmental factors and endogenous metabolic processes create polymerase-blocking DNA lesions, which can stall DNA replication machinery and cause genome instability. To avoid such events, cells have evolved a mechanism called translesion synthesis (TLS), which uses low fidelity polymerases to allow DNA synthesis across the lesions without actual repair. Our long-term goal is to understand regulatory mechanisms of TLS and determine its importance in prevention of genome instability and tumor formation. Recently, our group and others identified Spartan (also known as DVC1) as a novel regulator of TLS. We demonstrated that Spartan depletion results in accumulation of the error-prone TLS polymerase Pol zeta and higher UV-induced mutagenesis. Building on these observations, we now hypothesize that Spartan negatively regulates Pol zeta complex, and thereby prevents genome instability and tumor formation. To gain more insights into the mechanism of TLS regulation by Spartan and its physiological relevance, we propose to: (1) Study the mechanism of Pol zeta regulation by Spartan, (2) Investigate the cause of DNA damage and cell-cycle defects in Spartan knockout cells, (3) Examine the role of Spartan in genome stability and tumor suppression in mouse. Aim 1 will focus on the SprT domain, a putative metalloprotease domain of Spartan, and determine its role in Pol zeta regulation by characterizing its activity in vitro. n addition, we will investigate how Rev1, a regulator of Pol zeta, is involved in the complex formation of Pol zeta. In Aim 2, we will investigate the cause of DNA damage and cell cycle defects in Spartan knockout cells and determine whether it is related to Spartan's function in TLS. Finally in Aim 3, we will determine whether Spartan is important to prevent mutations, genome instability and tumor formation using mouse models. In summary, these studies will not only shed new light on the regulation of TLS by Spartan, but also provide novel insights into the role of TLS regulation in genome maintenance and tumor suppression.
描述(由申请人提供):环境因素和内源性代谢过程产生聚合酶阻断DNA病变,这可能会使DNA复制机制停滞并导致基因组不稳定。为了避免这些事件,细胞进化出了一种称为翻译合成(TLS)的机制,它使用低保真聚合酶来允许DNA合成跨越病变而无需实际修复。我们的长期目标是了解TLS的调控机制,并确定其在预防基因组不稳定和肿瘤形成中的重要性。最近,我们的研究小组和其他研究人员发现,Spartan(也称为DVC1)是一种新的TLS调节因子。我们证明,Spartan耗散导致易出错的TLS聚合酶Pol zeta的积累和更高的紫外线诱导诱变。基于这些观察,我们现在假设斯巴达负调控Pol zeta复合物,从而防止基因组不稳定和肿瘤形成。为了进一步了解Spartan调控TLS的机制及其生理相关性,我们建议:(1)研究Spartan调控Pol zeta的机制;(2)研究Spartan敲除细胞DNA损伤和细胞周期缺陷的原因;(3)研究Spartan在小鼠基因组稳定性和肿瘤抑制中的作用。目的1将重点关注SprT结构域,这是一种假定的斯巴达金属蛋白酶结构域,并通过表征其体外活性来确定其在Pol zeta调节中的作用。此外,我们将研究Pol zeta的调节因子Rev1如何参与Pol zeta的复杂形成。在Aim 2中,我们将研究Spartan敲除细胞中DNA损伤和细胞周期缺陷的原因,并确定其是否与Spartan在TLS中的功能有关。最后,在Aim 3中,我们将通过小鼠模型确定斯巴达对于预防突变、基因组不稳定和肿瘤形成是否重要。综上所述,这些研究不仅将为Spartan调控TLS提供新的思路,也将为TLS调控在基因组维持和肿瘤抑制中的作用提供新的见解。
项目成果
期刊论文数量(0)
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Yuichi Machida其他文献
Yuichi Machida的其他文献
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{{ truncateString('Yuichi Machida', 18)}}的其他基金
Regulation of polymerase switching in translesion synthesis
跨损伤合成中聚合酶转换的调节
- 批准号:
9191346 - 财政年份:2014
- 资助金额:
$ 32.99万 - 项目类别:
Regulation of polymerase switching in translesion synthesis
跨损伤合成中聚合酶转换的调节
- 批准号:
8609453 - 财政年份:2014
- 资助金额:
$ 32.99万 - 项目类别:
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