Broken chromosome segregation during mitosis: a Drosophila model
有丝分裂过程中染色体分离断裂:果蝇模型
基本信息
- 批准号:10444196
- 负责人:
- 金额:$ 31.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-22 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AreaBehaviorBiochemical GeneticsBiochemistryBiologicalBiological ModelsBiologyCell CycleCell DeathCell NucleusCell divisionCellsCentromereChildhoodChromosome CondensationChromosome SegregationChromosome StructuresChromosomesComplexDNADNA Double Strand BreakDNA RepairDNA Repair GeneDNA Repair PathwayDNA StructureDNA damage checkpointDNA-Directed DNA PolymeraseDataDefectDependenceDetectionDevelopmentDiseaseDisseminated Malignant NeoplasmDrosophila genusExhibitsFANCD2 proteinFaceFanconi&aposs AnemiaGeneticGenetic EpistasisGenetic ScreeningGenomeGenomic InstabilityGoalsHealthHumanImageImmunityInterphaseInterphase CellLaboratoriesLeftLinkMalignant NeoplasmsMammalian CellMediatingMetastatic toMitosisMitoticMitotic ChromosomeModelingMolecularMonoubiquitinationNatureOutcomePathway interactionsPhysical condensationPolymerasePositioning AttributeProcessPropertyProteinsProteomicsRegulationRoleSignal PathwaySiteSourceStructureSystemTestingTissuesWingWorkbasecondensinin vivoinnovationinsightinterestpreventrecruitrectalrepairedresponsescaffoldsegregationtargeted cancer therapytumor progressionubiquitin ligase
项目摘要
Chromosome double strand breaks (DSBs) that evade DNA damage checkpoints can persist into mitosis.
These DSBs are in danger of forming highly detrimental structures connected to genome shattering and tumor
progression, collectively referred to as micronuclei. To find mechanisms that prevent micronuclei, we discovered
that Drosophila papillar cells naturally inactivate DNA damage checkpoints, and as a result frequently exhibit
DNA fragments in mitosis. These fragments lack centromeres (acentric DNA), yet remarkably segregate during
papillar mitosis. This process prevents micronuclei and tissue development defects. The distinctive dependence
of papillar tissue development on acentric DNA segregation holds promise to reveal fundamental responses to
DSBs that persist into mitosis. From our combination of in vivo genetic screens, live imaging, and complementary
biochemistry approaches with collaborators, we are poised to make unique conceptual advances in this area.
This proposal leverages our expertise, new findings, and a genetically amenable Drosophila model to
uncover regulation of broken chromosome segregation. The significance of our proposed work is evident in the
frequent contribution of micronuclei to genome instability and the evolutionary conservation of the molecules
studied, including the Alternative End Joining (Alt-EJ) repair protein DNA Polymerase Theta, conserved
monoubiquitination of the DNA repair scaffold FancD2, and the ubiquitin ligase CRL4CDT2. The innovation of our
approach derives from our model system that is evolutionarily wired to solve the challenge of frequent persistent
broken chromosomes, and the enhanced in vivo genetic screening capability of our system. These advantages
led to the preliminary data presented in this proposal. In Aim1, we will define the pathway leading to poleward
segregation of acentric DNA. In this Aim, we will identify Pol Theta domains that function in acentric DNA
segregation, pinpoint the extent to which Alt-EJ occurs in papillar cells with DSBs, and assess the role of FancD2
in regulating Pol Theta after DSBs. In Aim2, we will define the signaling pathway that promotes the transition
from lagging to segregating acentric DNA. In this Aim, we will determine if CRL4CDT2 functions together with Pol
Theta/FancD2 to promote acentric DNA segregation, uncover whether critical regulation of CRL4CDT2 activity or
in papillar cells with DSBs, and assess if inactivity of interphase checkpoints leads to a requirement for CRL4CDT2
in segregating acentric DNA in a non-papillar cell context (wing cells). In Aim 3, we will determine how regulation
of mitotic chromosome condensation contributes to segregation of acentric DNA fragments. We will build on
biochemical, genetic, and protein localization data connecting CRL4CDT2 to the mitotic complex Condensin I. We
will assess the role of CRL4CDT2 in regulating Condensin I localization during acentric DNA segregation and
determine the role of a conserved CRL4CDT2 recognition sequence in Condensin I subunits. Collectively, our
approach will uncover fundamental regulation of broken mitotic DNA and can inform on disease-relevant biology.
逃避DNA损伤检查点的染色体双链断裂(DSB)可以持续到有丝分裂。
这些DSB有形成与基因组破碎和肿瘤相关的高度有害结构的危险
这一过程统称为微核。为了找到防止微核的机制,我们发现
果蝇的乳头状细胞自然地破坏DNA损伤检查点,因此经常表现出
有丝分裂中的DNA片段。这些片段缺乏着丝粒(无着丝粒DNA),但在生长过程中显著分离。
乳头状有丝分裂。这一过程可防止微核和组织发育缺陷。独特的依赖性
无着丝粒DNA分离的乳头状组织发育的承诺,揭示基本的反应,
持续到有丝分裂的DSB。从我们结合体内基因筛选,活成像,和互补
与合作者的生物化学方法,我们准备在这一领域取得独特的概念进展。
这项提议利用了我们的专业知识、新发现和一个遗传上适合的果蝇模型,
揭示染色体分离断裂的调控机制。我们建议的工作的重要性在以下方面显而易见:
微核对基因组不稳定性和分子进化保守性的频繁贡献
研究,包括交替末端连接(Alt-EJ)修复蛋白DNA聚合酶θ,保守的
DNA修复支架FancD 2的单泛素化和泛素连接酶CRL 4CDT 2。我们的创新
这种方法源自我们的模型系统,该模型系统在进化上被连接以解决频繁的持久性挑战。
断裂的染色体,以及我们系统的增强的体内遗传筛选能力。这些优势
导致了本提案中提出的初步数据。在目标1中,我们将定义通向极向的路径
无着丝粒DNA的分离。在这个目标中,我们将鉴定在无着丝粒DNA中起作用的Pol Theta结构域
分离,确定Alt-EJ在具有DSB的乳头状细胞中发生的程度,并评估FancD 2的作用
在DSB之后调节Pol Theta。在Aim 2中,我们将定义促进这种转变的信号通路。
从滞后到分离无着丝粒DNA。在这个目标中,我们将确定CRL 4CDT 2是否与Pol
Theta/FancD 2促进无着丝粒DNA分离,揭示CRL 4CDT 2活性的关键调节或
在具有DSB的乳头状细胞中,并评估间期检查点的不活动是否导致需要CRL 4 CDT 2
在分离无着丝粒DNA在非乳头状细胞的情况下(翼细胞)。在目标3中,我们将确定如何监管
有丝分裂染色体的凝聚有助于无着丝粒DNA片段的分离。我们将建立在
将CRL 4 CDT 2连接到有丝分裂复合体Condensin I的生化、遗传和蛋白定位数据。我们
将评估CRL 4CDT 2在无着丝粒DNA分离过程中调节凝聚蛋白I定位的作用,
确定一个保守的CRL 4CDT 2识别序列在凝聚蛋白I亚基中的作用。总体而言,我们
这种方法将揭示有丝分裂DNA断裂的基本调控,并可以为疾病相关生物学提供信息。
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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Donald T. Fox其他文献
Lessons of the Colombian Constitutional Reform of 1991 Toward the Securing of Peace and Reconciliation ?
1991 年哥伦比亚宪法改革的教训是为了确保和平与和解?
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
Donald T. Fox;Gustavo Gallón;Anne Stetson - 通讯作者:
Anne Stetson
Lineage analysis of stem cells
干细胞谱系分析
- DOI:
10.3824/stembook.1.33.1 - 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
Donald T. Fox;L. Morris;T. Nystul;A. Spradling - 通讯作者:
A. Spradling
Accelerated cell cycles enable organ regeneration under developmental time constraints in the Drosophila hindgut
加速的细胞周期使果蝇后肠在发育时间限制下实现器官再生
- DOI:
10.1101/2020.02.17.953075 - 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Erez Cohen;Donald T. Fox - 通讯作者:
Donald T. Fox
Cell Adhesion: Separation of p120's Powers?
细胞粘附:p120 权力的分离?
- DOI:
- 发表时间:
2007 - 期刊:
- 影响因子:9.2
- 作者:
Donald T. Fox;M. Peifer - 通讯作者:
M. Peifer
Balancing different types of actin polymerization at distinct sites
在不同位点平衡不同类型的肌动蛋白聚合
- DOI:
- 发表时间:
2003 - 期刊:
- 影响因子:7.8
- 作者:
E. Grevengoed;Donald T. Fox;J. Gates;M. Peifer - 通讯作者:
M. Peifer
Donald T. Fox的其他文献
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{{ truncateString('Donald T. Fox', 18)}}的其他基金
Broken chromosome segregation during mitosis: a Drosophila model
有丝分裂过程中染色体分离断裂:果蝇模型
- 批准号:
10708770 - 财政年份:2022
- 资助金额:
$ 31.01万 - 项目类别:
Novel tissue injury regulation at an organ-organ junction
器官-器官连接处的新型组织损伤调节
- 批准号:
9247216 - 财政年份:2016
- 资助金额:
$ 31.01万 - 项目类别:
Novel tissue injury regulation at an organ-organ junction
器官-器官连接处的新型组织损伤调节
- 批准号:
9894650 - 财政年份:2016
- 资助金额:
$ 31.01万 - 项目类别:
Polyploidy after tissue injury: a Drosophila model
组织损伤后的多倍体:果蝇模型
- 批准号:
10442828 - 财政年份:2016
- 资助金额:
$ 31.01万 - 项目类别:
Polyploidy after tissue injury: a Drosophila model
组织损伤后的多倍体:果蝇模型
- 批准号:
10848879 - 财政年份:2016
- 资助金额:
$ 31.01万 - 项目类别:
Polyploidy after tissue injury: a Drosophila model
组织损伤后的多倍体:果蝇模型
- 批准号:
10598614 - 财政年份:2016
- 资助金额:
$ 31.01万 - 项目类别:
Novel tissue injury regulation at an organ-organ junction
器官-器官连接处的新型组织损伤调节
- 批准号:
9078527 - 财政年份:2016
- 资助金额:
$ 31.01万 - 项目类别:
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