Regulation of genome replication, recombination, and stress response
Regulation of genome replication, recombination, and stress response
批准号:
10809252
负责人:
Xiaolan Zhao
金额:
$14.17万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-20 至 2027-08-31
关键词:
AddressAdoptedAffectAreaBiochemicalBiological AssayCellsChromatin LoopCollaborationsComplexComprehensionCoupledCruciform DNADNADNA BindingDNA Binding DomainDNA DamageDNA Double Strand BreakDNA RepairDNA StructureDNA biosynthesisDNA damage checkpointDNA replication forkDataDevelopmentDiseaseDouble Strand Break RepairEnsureEnzymesExcisionFailureFamilyFamily memberGenetic RecombinationGenomeGenome StabilityGenomic InstabilityGenomicsGoalsGrowthHumanInvadedJointsLeftLicensingLinkMalignant NeoplasmsMethodsMolecularMutagensMutationNatureOutcomeOutcome StudyPathway interactionsProcessProtein FamilyProteinsRNARad51 recombinaseRegulationResearchResolutionRibosomal DNARoleSequence HomologsSignal TransductionSingle-Stranded DNASiteSpeedStressStructureSyndromeSystemTestingTimeTopoisomerase IIIWorkYeastsbiological adaptation to stresscofactorcopingcoping mechanismds-DNAgenetic manipulationhelicasehomologous recombinationhuman diseaseinsightinterdisciplinary approachmembermigrationnovelnovel strategiespreventrecombinational repairrepairedresponsesingle moleculetelomeretooltumorigenesis
中文摘要
维持基因组稳定性需要 DNA 复制、DNA 修复和 DNA 的复杂协调
损害反应。我们开发了多学科方法来研究一些复杂的 DNA
这些过程中的交易和信号传递人们知之甚少。我们的调查领域包括
复制体和复制叉的调节,同源重组中间体的控制,以及
抑制 DNA 损伤反应。我们的研究结果提出了新的假设,并对其进行测试
加深我们对关键基因组调控策略的理解。
DNA 复制必须应对多种类型的模板障碍。应对机制需要密切
复制体和许多监管机构之间的合作。我们的长期目标之一是阐明如何
各种调节器动态地修改复制体功能。我们将应用新的策略来识别复制体
变化并确定高度保守的多功能 Smc5/6 复合物如何促进复制体
功能。我们研究的另一个目标是确定在编程时停滞的复制叉的控制
核糖体DNA内的屏障。这些站点遭受拓扑应力,可能导致分叉不稳定。我们会
研究细胞在面对完成复制的挑战时如何维持停滞的复制叉。
当复制叉因屏障而停滞而无法恢复时,折叠的叉和未复制的 DNA 间隙可能会被修复。
通过同源重组进行修复,产生修复中间体,例如霍利迪连接体。解决
这种联合DNA结构通过专门的裂解酶完成修复过程并防止DNA
纠缠。这些酶与一系列调节因子协同作用,实现有效的修复;然而,
许多调节剂的分子作用仍不清楚。我们的目标是阐明其背后的机制
这些调节器的作用,包括功能耦合的 Smc5/6 和 Esc2。此外。我们将学习
Smc5/6,在分子细节上将 DNA 复制和重组控制联系在一起。
DNA 复制和修复失败引起的基因组应激会激活 DNA 损伤检查点。同时
激活这个检查点是有益的,它的持续存在对生长有害。抑制 DNA 损伤
因此,检查点对于对抗此类有害影响至关重要,但其机制尚未得到充分研究。我们的一员
研究目标是确定检查点抑制途径及其许可机制。这条线的
研究将为 DNA 损伤检查点的动态控制提供见解。
我们提出的研究结果将扩大我们对相互关联的基因组复制、修复和
应激反应过程,并为与这些途径故障相关的疾病研究提供信息。
英文摘要
Maintaining genome stability requires the intricate coordination of DNA replication, DNA repair, and the DNA
damage response. We have developed multi-disciplinary approaches to investigate some of the complex DNA
transactions and signaling in these processes that are poorly understood. Our areas of inquiry include the
regulation of the replisome and replication forks, the control of homologous recombination intermediates, and
dampening of the DNA damage response. Our findings have led to novel hypotheses and testing them will
deepen our understanding of critical genome regulation strategies.
DNA replication must cope with many types of template barriers. The coping mechanisms entail close
collaboration between the replisome and many regulators. One of our long-term goals is to elucidate how
various regulators dynamically modify replisome functions. We will apply novel strategies to identify replisome
changes and determine how the highly conserved multi-functional Smc5/6 complex promotes replisome
function. Another goal of our studies is to determine the control of replication forks stalled at programmed
barriers within the ribosomal DNA. These sites suffer topological stress that can drive fork instability. We will
investigate how cells maintain the stalled replication forks in the face of this challenge to complete replication.
When replication forks stalled by barriers fail to recover, collapsed forks and unreplicated DNA gaps can be
repaired by homologous recombination, generating repair intermediates such as Holliday junctions. Resolving
such joint DNA structures by specialized cleavage enzymes completes the repair process and prevents DNA
entanglement. These enzymes collaborate with a range of regulators to engender efficient repair; however, the
molecular roles of many regulators remain unclear. It is our goal to elucidate the mechanisms underlying the
roles of these regulators, including the functionally coupled Smc5/6 and Esc2. In addition. we will study
Smc5/6, which ties together DNA replication and recombinational control, in molecular detail.
Genomic stress caused by DNA replication and repair failure activates the DNA damage checkpoint. While
activating this checkpoint is beneficial, its persistence is detrimental to growth. Dampening the DNA damage
checkpoint is thus essential to counter such harmful effects, but its mechanisms are understudied. One of our
research goals is to identify checkpoint dampening pathways and their licensing mechanisms. This line of
study will provide insights into the dynamic control of the DNA damage checkpoint.
Outcomes of our proposed studies will expand our view of interconnected genome replication, repair, and
stress response processes and inform studies of diseases that are linked to the malfunction of these pathways.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1038/s41467-022-34045-7
发表时间:
2022-10-27
期刊:
NATURE COMMUNICATIONS
影响因子:
16.6
作者:
[Li, Mu, Zhong, Aaron, Wu, Youjun, Sidharta, Mega, Beaury, Michael, Zhao, Xiaolan, Studer, Lorenz, Zhou, Ting]
通讯作者:
Zhou, Ting
Regulation of genome replication, recombination, and stress response
-
批准号:10406632
-
项目类别:
-
资助金额:$44.25万
-
财政年份:2022
-
负责人:Xiaolan Zhao
-
依托单位:
Regulation of genome replication, recombination, and stress response
-
批准号:10707021
-
项目类别:
-
资助金额:$70.8万
-
财政年份:2022
-
负责人:Xiaolan Zhao
-
依托单位:
Regulation of replication and recombination intermediates
-
批准号:10153821
-
项目类别:
-
资助金额:$35.92万
-
财政年份:2019
-
负责人:Xiaolan Zhao
-
依托单位:
Regulation of Replication and Recombination Intermediates
-
批准号:10414197
-
项目类别:
-
资助金额:$7.53万
-
财政年份:2019
-
负责人:Xiaolan Zhao
-
依托单位:
Regulation of replication and recombination intermediates
-
批准号:10689591
-
项目类别:
-
资助金额:$10.05万
-
财政年份:2019
-
负责人:Xiaolan Zhao
-
依托单位:
Regulation of replication and recombination intermediates
-
批准号:10406889
-
项目类别:
-
资助金额:$35.92万
-
财政年份:2019
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
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批准号:8009924
-
项目类别:
-
资助金额:$3.45万
-
财政年份:2010
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
-
批准号:9196359
-
项目类别:
-
资助金额:$35.57万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
-
批准号:7673498
-
项目类别:
-
资助金额:$30.25万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
-
批准号:7498480
-
项目类别:
-
资助金额:$30.25万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
-
批准号:8991319
-
项目类别:
-
资助金额:$35.57万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
-
批准号:8130728
-
项目类别:
-
资助金额:$29.65万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
-
批准号:8632499
-
项目类别:
-
资助金额:$35.57万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
-
批准号:8792535
-
项目类别:
-
资助金额:$35.57万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
-
批准号:7384433
-
项目类别:
-
资助金额:$30.39万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
Studies of the Smc5/Smc6 complex in chromosomal replication
-
批准号:7903094
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项目类别:
-
资助金额:$29.95万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
The Rtt107 interactome structures and functions
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批准号:10079485
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项目类别:
-
资助金额:$39.51万
-
财政年份:2007
-
负责人:Xiaolan Zhao
-
依托单位:
海外基金