Ins and Outs of Abscission Checkpoint Signaling: Molecular Mechanisms Safeguarding Abscission
脱落检查点信号的来龙去脉:保护脱落的分子机制
基本信息
- 批准号:10710793
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAutophagocytosisBiological AssayCell Cycle CheckpointCell ProliferationCellsChromosomal BreaksChromosome SegregationCoupledDNADNA DamageDNA biosynthesisDevelopmentDiagnosisDiseaseEnsureEventExcisionLinkMaintenanceMalignant NeoplasmsMetabolicMitosisMitoticMolecularNuclear PorePathway interactionsPost-Translational Protein ProcessingProteinsRegulationResearchSignal PathwaySignal TransductionStructureTherapeuticWorkcancer celldaughter cellglucose metabolisminnovationinsightinterdisciplinary approachmicronucleusnovelphysical separationprematureprogramsrecruit
项目摘要
PROJECT SUMMARY:
Cytokinetic abscission is the physical separation of daughter cells that concludes mitosis. Premature abscission
in the presence of incompletely segregated chromosomes can result in chromosome breaks that give rise to
DNA damage and micronuclei which are hallmarks of cancer. To ensure that the onset of cytokinetic abscission
is synchronized with the completion of upstream mitotic events, cells have evolved a cell cycle checkpoint known
as the abscission checkpoint. Cells arrest abscission in the presence of mitotic errors such as trapped DNA in
the intercellular bridge, mis formed nuclear pores, under-replicated DNA, and tension at the intercellular bridge.
In this proposal we take an innovative multidisciplinary approach that combines structure function studies with
cell-based assays to address major outstanding questions underlying abscission checkpoint regulation, including
how cells sense checkpoint triggers, and how protective activities are coupled with abscission. In Focus 1, we
will use a structure-function approach to understand the mechanism whereby the ESCRT abscission machinery
recruits and triggers novel cellular autophagy pathways. In Focus 2 we will examine how the metabolic status of
a cell can lead to post-translational modification of abscission checkpoint proteins to alter the fidelity of
abscission, providing the first direct links between glucose metabolism and abscission checkpoint function.
Taken together, this work will provide essential mechanistic, molecular-level insight into how cells promote
faithful abscission, how the mistakes in abscission can lead to the development of cancer, and ultimately, suggest
therapeutic strategies for combatting cancer cell proliferation.
项目总结:
项目成果
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