Ins and Outs of Abscission Checkpoint Signaling: Molecular Mechanisms Safeguarding Abscission

项目总结:

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.