Mechanisms of Chromosome Scale Signal Propagation
染色体尺度信号传播的机制
基本信息
- 批准号:10217794
- 负责人:
- 金额:$ 4.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-03-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAnimal ModelBindingBirdsCellsChromatinChromosomal BreaksChromosomal InstabilityChromosome SegregationChromosomesCommunicationCongenital AbnormalityCytologyDNADNA Double Strand BreakDangerousnessDataDefectDouble Strand Break RepairDown SyndromeDown-RegulationEdward&aposs syndromeEnsureEventFertilityFundingGenesGeneticGenetic EpistasisGenetic NondisjunctionGenetic RecombinationGenetic TranscriptionGenetic VariationGenomeGenomic SegmentGenomicsGerm CellsGoalsHumanHuman ChromosomesIncidenceInfertilityLeadLengthMammalsMeiosisMeiotic RecombinationMicroscopyModelingMolecularNuclearNuclear EnvelopeNuclear PoreOrganismPan GenusPatternProcessProductionProphaseProteinsRegulationResearchResistanceResolutionRestRiskRoleSaccharomyces cerevisiaeSignal TransductionStructureSynaptonemal ComplexTestingWorkYeastseggenzyme activityexperimental studygenome integritygenome-wide analysisimprovedinsightinterstitialnovelrepairedsegregationsperm celltelomeretumor progression
项目摘要
Project summary
The overall goal of this project is to determine how cells communicate chromosome break formation and
repair across large chromosomal distances. DNA double-strand breaks (DSBs) are dangerous insults to
genome integrity because of their potential to cause chromosome rearrangements and chromosome instability,
both of which are strongly associated with cancer progression as well as birth defects. Remarkably, meiotic
cells are able to efficiently orchestrate the formation and repair of hundreds of concurrent DSBs across their
genome during meiotic recombination, a process that is essential for proper gamete formation and fertility.
A key feature of meiotic DSB formation and repair is its coordination at the chromosomal level. In the
previous funding period we provided evidence that the synaptonemal complex, a conserved protein lattice that
forms between aligned homologous chromosomes in late meiotic prophase, communicates repair decisions
along meiotic chromosomes in S. cerevisiae. We showed that this communication resulted in reduced DSB
formation as well as simplified repair, and we identified several factors involved in this process. We now
discovered the existence of privileged genomic regions near the ends of all chromosomes that appear resistant
to regulation by the synaptonemal complex. These end-adjacent regions (EARs) cover large genomic
distances (~100kb, which is nearly half the length of the shortest chromosome) and continue to form and repair
DSBs well after DSB formation has stopped in the rest of the genome. Similar regions of elevated meiotic
recombination are also observed in birds, chimps, and humans.
The goal of this project is to define the chromosomal signal that generates these regions and to test if
EARs help inheritance of short chromosomes. Our preliminary analyses suggest several roles of the nuclear
envelope, both in the establishment of the EARs and in the suppression of DSBs in the rest of the genome.
The dynamics of chromosomal signaling and its interaction with the nuclear envelope will be analyzed by
genome-wide binding studies and super-resolution microscopy, taking advantage of a conditional nuclear
depletion approach that we recently introduced into meiotic cells that allows stage-specific knock-downs of
pleiotropic nuclear factors. In addition, signal integration will be analyzed using genetic epistasis analyses,
cytology, and physical analysis of DSB formation. As EARs cover a proportionally much larger fraction of short
chromosomes, the proposal will also use tetrad sequencing to test if these regions drive the widely observed
increase in recombination rates on short chromosomes. Fluorescent marker segregation will be used to
determine if EARs differentially improve the meiotic segregation fidelity of short chromosomes. Together, these
analyses will provide key insights into the mechanisms of chromosomal signal propagation, and open new
avenues for understanding the origins of birth defects such as Down syndrome (trisomy 21) and Edwards
syndrome (trisomy 18), which are caused by meiotic missegregation of short chromosomes.
项目摘要
该项目的总体目标是确定细胞如何交流染色体断裂形成和
修理大型染色体距离。 DNA双链断裂(DSB)是危险的侮辱
基因组完整性是因为它们有可能引起染色体重排和染色体不稳定性的潜力
两者都与癌症进展以及先天缺陷密切相关。值得注意的是,减数分裂
细胞能够有效地编排数百个并发DSB的形成和修复
减数分裂重组期间的基因组,这对于适当的配子形成和生育力至关重要。
减数分裂DSB形成和修复的关键特征是在染色体水平上的协调。在
以前的资金期我们提供了证据,表明Synaptonemal复合体是一种保守的蛋白质晶格,
在减数分裂预言的晚期同源染色体之间的形式,交流维修决策
沿着酿酒酵母中的减数分裂染色体。我们证明了这种沟通导致DSB减少
形成以及简化的维修,我们确定了此过程中涉及的几个因素。我们现在
发现了所有抗抗性的末端附近的特权基因组区域的存在
通过突发型复合物调节。这些末端粘合区域(EAR)覆盖了大型基因组
距离(〜100KB,几乎是最短染色体的一半),并继续形成和修复
DSB形成在基因组的其余部分停止后,DSB远。类似的减数分裂升高区域
在鸟类,黑猩猩和人类中也观察到重组。
该项目的目的是定义生成这些区域的染色体信号,并测试是否
耳朵有助于遗传短染色体。我们的初步分析表明核的几个作用
包络,无论是在耳朵的建立还是在基因组的其余部分中抑制DSB的象征。
染色体信号传导的动力学及其与核包膜的相互作用将通过
全基因组结合研究和超分辨率显微镜,利用条件核
我们最近引入的减数分裂细胞的耗竭方法,该方法允许阶段特定的敲击
多效性核因素。此外,将使用遗传上毒分析来分析信号积分,
DSB形成的细胞学和物理分析。由于耳朵覆盖了一小部分短。
染色体,该提案还将使用四四型测序来测试这些区域是否驱动了广泛观察到的
短染色体上的重组率增加。荧光标记物分离将用于
确定耳朵是否差异改善了短染色体的减数分裂隔离保真度。在一起,这些
分析将提供有关染色体信号传播机制的关键见解,并开放新的
理解先天缺陷的起源的途径,例如唐氏综合症(三体疾病)和爱德华兹(Edwards)
综合征(第18三体),是由短染色体的减数分裂错误分析引起的。
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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Andreas Hochwagen其他文献
Andreas Hochwagen的其他文献
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{{ truncateString('Andreas Hochwagen', 18)}}的其他基金
Chromosomal control of meiotic double-strand break formation
减数分裂双链断裂形成的染色体控制
- 批准号:
10078609 - 财政年份:2018
- 资助金额:
$ 4.09万 - 项目类别:
Mechanisms of Chromosome Scale Signal Propagation
染色体尺度信号传播的机制
- 批准号:
10172920 - 财政年份:2015
- 资助金额:
$ 4.09万 - 项目类别:
Mechanisms of Chromosome Scale Signal Propagation
染色体尺度信号传播的机制
- 批准号:
10403654 - 财政年份:2015
- 资助金额:
$ 4.09万 - 项目类别:
Mechanisms of Chromosome Scale Signal Propagation
染色体尺度信号传播的机制
- 批准号:
10620977 - 财政年份:2015
- 资助金额:
$ 4.09万 - 项目类别:
Mechanisms of Chromosome Scale Signal Propagation
染色体尺度信号传播的机制
- 批准号:
10001534 - 财政年份:2015
- 资助金额:
$ 4.09万 - 项目类别:
Control of meiotic double strand break formation
减数分裂双链断裂形成的控制
- 批准号:
8535164 - 财政年份:2010
- 资助金额:
$ 4.09万 - 项目类别:
Control of meiotic double strand break formation
减数分裂双链断裂形成的控制
- 批准号:
8041361 - 财政年份:2010
- 资助金额:
$ 4.09万 - 项目类别:
Control of meiotic double strand break formation
减数分裂双链断裂形成的控制
- 批准号:
8425479 - 财政年份:2010
- 资助金额:
$ 4.09万 - 项目类别:
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