Replication checkpoint activation and silencing
复制检查点激活和静默
基本信息
- 批准号:7900280
- 负责人:
- 金额:$ 9.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-13 至 2010-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATM Signaling PathwayATM activationATR protein kinaseAntineoplastic AgentsAttenuatedBiochemicalBiochemical GeneticsBiological AssayBypassCaenorhabditis elegansCancer EtiologyCell CycleCell Cycle CheckpointCell Division ProcessCellsChromosomal BreaksChromosomal translocationChromosome BreakageChromosomesComplexDNADNA DamageDNA Polymerase IDNA biosynthesisDNA-Directed DNA PolymeraseEmbryoEventGeneticGenetic MaterialsGenetic ScreeningGenome StabilityGoalsHumanLaboratoriesLeadLeftLesionMaintenanceMediatingMolecularNormal CellOrthologous GenePathway interactionsPhasePhysiologicalPlayPolymeraseProcessProtein KinaseProteinsRad30 proteinRecruitment ActivityRegulationReplication-Associated ProcessRoleS PhaseSignal PathwaySignal TransductionSiteStressSystemXenopusbasecancer cellchromosome replicationegggenetic analysismeetingsnovelpublic health relevancerepairedresponseubiquitin ligaseubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): The process of DNA replication during S phase of the cell cycle is constantly challenged by the presence of damaged DNA on the replication template. Base lesions in chromosomes can cause DNA polymerase stalling, and if the stalled polymerase is not resolved than the replication fork will collapse, and the chromosome will be broken. Collapsed replication forks are, therefore, a serious threat to the maintenance of genome stability, and are thought to be a primary event in generating the genetic instability that allows normal cells to become cancer cells. In this project, we will focus on two important pathways that allow cells to tolerate DNA damage during S phase, the ATM and Rad3 related (ATR)- dependent replication checkpoint, and the DNA polymerase eta-dependent trans- lesion synthesis (TLS) damage bypass pathway. Recent results from my laboratory have revealed that these two pathways interact during a DNA damage response and, in particular, that pol eta can override the activation of ATR by DNA damage. In this project, we will focus on how ATR is activated by stalled forks, by studying the critical ATR activator TopBP1. We have found that TopBP1 senses the stalled fork, and that it recruits DNA polymerase alpha (pol 1) and the 911 complex to the stalled fork. Recruitment of these two factors by TopBP1 is required for ATR activation. In Aim 1, we will investigate the molecular mechanism whereby TopBP1 senses stalled forks, and in Aim 2 we will probe the biochemical mechanism for how it then recruits pol 1 and 911. In Aim 3, we will investigate how pol eta overrides the ATR response to DNA damage, and in Aim 4 we will investigate a novel, proteolytic-based mechanism that regulates pol eta function during the DNA damage response. If these goals are met, then we will have achieved a greater understanding of the molecular mechanisms involved in ATR activation, and in pol eta regulation. Importantly, we will have also increased out understanding of how the ATR and pol eta pathways interact, and this will allow for a more integrated view of how cells manage replication stress to emerge.
PUBLIC HEALTH RELEVANCE: DNA damage is a serious impediment to chromosome replication, a fundamental component of the process of cell division. When DNA damage is encountered during chromosome replication, it will stall the DNA polymerases that are responsible for duplication of the genetic material. This stalling can have severe consequences for the stability of the genome, as a stalled polymerase that is left unresolved can cause the replication process to collapse, and the chromosome to break. The repair of broken chromosomes can be imperfect, and can than thereby result in the chromosome translocations that are known to cause cancer. In this proposal, we focus on two cellular pathways that help cells deal with stalled polymerases. One is a signaling pathway, and we will study how this signaling pathway recognizes stalled polymerases and, how it is activated by them. The other pathway involves a specialized DNA polymerase that can replicate DNA even when it is damaged. We will study the regulation of this polymerase, and the ability of this polymerase to influence signaling that is derived from stalled replication. These studies will help us understand how cells manage stalled replication, and could form the basis for newer and more effective anti-cancer drugs.
描述(申请人提供):在细胞周期的S阶段,DNA复制过程不断地受到复制模板上损伤DNA的存在的挑战。染色体中的碱基损伤会导致DNA聚合酶停滞,如果停滞的聚合酶得不到解决,复制叉就会坍塌,染色体就会断裂。因此,倒塌的复制叉子是对维持基因组稳定性的严重威胁,并被认为是导致正常细胞成为癌细胞的遗传不稳定性的主要事件。在本项目中,我们将重点研究两条允许细胞在S期耐受DNA损伤的重要途径,即依赖atm和Rad3(Atr)的复制检查点和依赖于DNA聚合酶eta的跨损伤合成(TLS)损伤旁路。我的实验室最近的研究结果表明,这两条途径在DNA损伤反应中相互作用,特别是polETA可以通过DNA损伤覆盖ATR的激活。在这个项目中,我们将通过研究关键的ATR激活剂TopBP1,重点研究ATR是如何被失速的叉子激活的。我们发现TopBP1感知失速的叉子,并将DNA聚合酶α(Pol1)和911复合体招募到失速的叉子上。ATR的激活需要TopBP1招募这两个因子。在目标1中,我们将研究TopBP1感知失速叉子的分子机制,在目标2中,我们将探索它如何招募Pol1和911的生化机制。在目标3中,我们将研究PolETA如何覆盖ATR对DNA损伤的响应,在目标4中,我们将研究一种新的、基于蛋白质分解的机制,它在DNA损伤反应中调节PolETA的功能。如果这些目标得以实现,那么我们将对ATR激活和PolETA调控的分子机制有更好的理解。重要的是,我们还将增加对ATR和polETA通路如何相互作用的理解,这将使我们能够对细胞如何管理复制应激有一个更完整的看法。
与公共卫生相关:DNA损伤是染色体复制的严重障碍,而染色体复制是细胞分裂过程的基本组成部分。当在染色体复制过程中遇到DNA损伤时,它会使负责复制遗传物质的DNA聚合酶停滞。这种停滞可能会对基因组的稳定性产生严重的后果,因为停滞的聚合酶如果没有被分解,可能会导致复制过程崩溃,染色体断裂。对断裂的染色体的修复可能不完善,从而可能导致已知的致癌染色体易位。在这个提案中,我们专注于帮助细胞处理停滞的聚合酶的两条细胞途径。一个是信号通路,我们将研究这个信号通路如何识别停滞的聚合酶,以及如何被它们激活。另一种途径涉及一种特殊的DNA聚合酶,即使DNA受损,它也可以复制DNA。我们将研究这种聚合酶的调节,以及这种聚合酶影响来自停滞复制的信号的能力。这些研究将帮助我们了解细胞如何管理停滞的复制,并可能形成新的和更有效的抗癌药物的基础。
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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MATTHEW MICHAEL其他文献
MATTHEW MICHAEL的其他文献
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{{ truncateString('MATTHEW MICHAEL', 18)}}的其他基金
Molecular mechanisms for germline genome activation in C. elegans
线虫种系基因组激活的分子机制
- 批准号:
10092192 - 财政年份:2019
- 资助金额:
$ 9.44万 - 项目类别:
Molecular mechanisms for germline genome activation in C. elegans
线虫种系基因组激活的分子机制
- 批准号:
10081929 - 财政年份:2019
- 资助金额:
$ 9.44万 - 项目类别:
Molecular mechanisms for germline genome activation in C. elegans
线虫种系基因组激活的分子机制
- 批准号:
10337245 - 财政年份:2019
- 资助金额:
$ 9.44万 - 项目类别:
ATR-Chk1 signaling during embryonic and germ line development in C. elegans
秀丽隐杆线虫胚胎和种系发育过程中的 ATR-Chk1 信号传导
- 批准号:
8218081 - 财政年份:2012
- 资助金额:
$ 9.44万 - 项目类别:
ATR-Chk1 signaling during embryonic and germ line development in C. elegans
秀丽隐杆线虫胚胎和种系发育过程中的 ATR-Chk1 信号传导
- 批准号:
8415514 - 财政年份:2012
- 资助金额:
$ 9.44万 - 项目类别:
ATR-Chk1 signaling during embryonic and germ line development in C. elegans
秀丽隐杆线虫胚胎和种系发育过程中的 ATR-Chk1 信号传导
- 批准号:
8610930 - 财政年份:2012
- 资助金额:
$ 9.44万 - 项目类别:
ATR-Chk1 signaling during embryonic and germ line development in C. elegans
秀丽隐杆线虫胚胎和种系发育过程中的 ATR-Chk1 信号传导
- 批准号:
8798672 - 财政年份:2012
- 资助金额:
$ 9.44万 - 项目类别:
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