Mechanisms of cohesin regulation in vertebrates
Mechanisms of cohesin regulation in vertebrates
批准号:
10623786
负责人:
Susannah Rankin
金额:
$42.63万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-04-03 至 2028-03-31
关键词:
AddressCell NucleusCell divisionCellsChromosome SegregationChromosomesCultured CellsDNA DamageDNA RepairDNA biosynthesisDNA replication forkDevelopmentEmbryoEnsureEukaryotaFundingGene ExpressionGenetic TranscriptionGenomeIn VitroMaintenanceMediatingModelingModificationMolecularMolecular GeneticsNuclear StructureOrthologous GeneOutcomePeptide Initiation FactorsPlayProcessProteinsRanaRegulationRoleSignal TransductionSister ChromatidSiteSystemTestingVertebratesWorkcohesincohesionegggenetic approachprotein complexprotein purification
中文摘要
项目概要/摘要
在脊椎动物细胞中,粘附蛋白复合物在核结构和功能中起关键作用。它束缚着
DNA复制的相同产物,称为姐妹染色单体,直到细胞分裂,它也
介导染色体内桥接相互作用,形成染色体环和结构域。虽然凝聚力
姐妹染色单体之间的相互作用对于精确的染色体分离和某些类型的DNA修复至关重要,
染色体压缩成环和结构域对于正确的转录和正常的转录是必需的。
发展这些不同种类的凝聚力在分子水平上是如何不同的,
每一个结果,以及它们之间的重叠量都没有得到很好的理解。存在多
许多粘附素亚基和调节子的直系同源物,以及Sororin的存在,这是独特的
后生动物,表明在高等真核生物中的复杂性的粘附调节。我们的工作解决了几个关键问题
该领域的挑战:1)DNA复制和粘着蛋白调节如何在脊椎动物中正确整合
细胞,2)脊椎动物特有的内聚器如何有助于功能,以及3)如何
粘着蛋白是否可以局部重塑以确保特定的结果,例如基因表达或通路的变化
和DNA修复机制的功能。和以前一样,我们将继续在多个系统中工作,
适当的,包括基因组修饰的培养细胞,来自青蛙卵的无细胞裂解物,青蛙胚胎,
体外纯化蛋白质。我们的优势在于使用分子遗传学方法,
在所有这些实验系统中,特定相互作用的影响。通过跟进我们最近的工作,
在下一个资助期结束时,我们希望能够完全了解ESCO 1和ESCO 2脊椎动物
内聚蛋白修饰剂,通过其惊人的非结构化结构域,稳定在特定的上下文中的内聚,
方式我们还将定义DNA复制叉处的蛋白质,特别是起始因子TICRR,
影响粘着蛋白的稳定性,以及在早期发育过程中对该过程的调节。最后,我们将利用
脊椎动物粘着蛋白对位点特异性DNA损伤的作用
调节剂和修饰损伤诱导的局部粘连蛋白重塑,从而基因组的维护。
英文摘要
Project Summary/Abstract
In vertebrate cells the cohesin protein complex plays critical roles in nuclear structure and function. It tethers
together the identical products of DNA replication, called sister chromatids, until cell division and it also
mediates intra-chromosomal bridging interactions, forming chromosome loops and domains. While cohesion
between sister chromatids is critical for accurate chromosome segregation and certain kinds of DNA repair, the
compaction of chromosomes into loops and domains is essential for proper transcription and normal
development. How these different kinds of cohesion differ at the molecular level, the mechanisms that ensure
each outcome, and the amount of overlap between them are not well understood. The existence of multiple
orthologs of a number of cohesin subunits and regulators, as well as the presence of Sororin, which is unique
to metazoans, suggest complexity of cohesin regulation in higher eukaryotes. Our work addresses several key
challenges in the field: 1) how are DNA replication and cohesin regulation properly integrated in vertebrate
cells, 2) how do vertebrate-specific elaborations of the cohesion apparatus contribute to function, and 3) how
can cohesin be remodeled locally to ensure specific outcomes, such as changes in gene expression or access
and function of DNA repair machinery. As previously, we will continue to work in multiple systems as
appropriate, including genome-modified cultured cells, cell free lysates from frog eggs, frog embryos, and
purified proteins in vitro. Our strength lies in using molecular genetic approaches that allow us to test directly
the impacts of specific interactions, in all of these experimental systems. By following up on our recent work, at
the end of this next funding period we hope to fully understand how the ESCO1 and ESCO2 vertebrate
cohesin modifiers, through their strikingly unstructured domains, stabilize cohesion in a context-specific
manner. We will also define how proteins at the DNA replication fork, particularly the initiation factor TICRR,
impact cohesin stabilization, and the regulation of this process during early development. Finally, we will exploit
a tractable model for site-specific DNA damage to characterize the contributions of vertebrate cohesin
regulators and modifications to damage-induced local cohesin remodeling and thus genome maintenance.
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会议论文
Mechanisms of cohesin regulation in vertebrates
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批准号:10855552
-
项目类别:
-
资助金额:$6.13万
-
财政年份:2023
-
负责人:Susannah Rankin
-
依托单位:
Regulation of chromosome cohesion during cell cycle progression
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批准号:10318566
-
项目类别:
-
资助金额:$36.71万
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财政年份:2013
-
负责人:Susannah Rankin
-
依托单位:
Regulation of chromosome cohesion during cell cycle progression
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批准号:10530862
-
项目类别:
-
资助金额:$4.39万
-
财政年份:2013
-
负责人:Susannah Rankin
-
依托单位:
Regulation of Chromosome Cohesion during Cell Cycle Progression
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批准号:9094657
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项目类别:
-
资助金额:$30.24万
-
财政年份:2013
-
负责人:Susannah Rankin
-
依托单位:
Regulation of Chromosome Cohesion during Cell Cycle Progression
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批准号:8876718
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项目类别:
-
资助金额:$30.24万
-
财政年份:2013
-
负责人:Susannah Rankin
-
依托单位:
Cohesin and chromosome translocation
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批准号:10315206
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项目类别:
-
资助金额:$3.66万
-
财政年份:2013
-
负责人:Susannah Rankin
-
依托单位:
Regulation of chromosome cohesion during cell cycle progression
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批准号:9918789
-
项目类别:
-
资助金额:$12.12万
-
财政年份:2013
-
负责人:Susannah Rankin
-
依托单位:
Regulation of Chromosome Cohesion during Cell Cycle Progression
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批准号:8506325
-
项目类别:
-
资助金额:$30.24万
-
财政年份:2013
-
负责人:Susannah Rankin
-
依托单位:
Regulation of Chromosome Cohesion during Cell Cycle Progression
-
批准号:9295032
-
项目类别:
-
资助金额:$30.24万
-
财政年份:2013
-
负责人:Susannah Rankin
-
依托单位:
Regulation of Chromosome Cohesion during Cell Cycle Progression
-
批准号:8670759
-
项目类别:
-
资助金额:$30.24万
-
财政年份:2013
-
负责人:Susannah Rankin
-
依托单位:
SISTER CHROMATID COHESION AND THE ORIGIN OF TETRAPLOIDY
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批准号:8359632
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项目类别:
-
资助金额:$8.42万
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财政年份:2011
-
负责人:Susannah Rankin
-
依托单位:
SISTER CHROMATID COHESION AND THE ORIGIN OF TETRAPLOIDY
-
批准号:8167531
-
项目类别:
-
资助金额:$10.58万
-
财政年份:2010
-
负责人:Susannah Rankin
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依托单位:
DIPLOCHROMOSOMES: ORIGINS AND SEGREGATION BEHAVIOR
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批准号:7960026
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项目类别:
-
资助金额:$11.2万
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财政年份:2009
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负责人:Susannah Rankin
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依托单位:
DIPLOCHROMOSOMES: ORIGINS AND SEGREGATION BEHAVIOR
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批准号:7725104
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项目类别:
-
资助金额:$10.17万
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财政年份:2008
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负责人:Susannah Rankin
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依托单位:
DIPLOCHROMOSOMES: ORIGINS AND SEGREGATION BEHAVIOR
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批准号:7610288
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项目类别:
-
资助金额:$5.03万
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财政年份:2007
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负责人:Susannah Rankin
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依托单位:
EFFECTS OF CORNELIA DE LANGE-ASSOCIATED GENOTYPES ON CELL CYCLE CONTROL
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批准号:7610292
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项目类别:
-
资助金额:$2.42万
-
财政年份:2007
-
负责人:Susannah Rankin
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依托单位:
海外基金