Molecular bases of kinetochore-microtubule attachm.. (KINCON)
Molecular bases of kinetochore-microtubule attachment and their implications for cell cycle control
Start date: Mar 1, 2009,
End date: Sep 30, 2014
Equal partition of the genetic material to the daughter cells in mitosis requires the accurate anchorage of the mother cell s chromosomes to spindle microtubules. This process takes place at kinetochores, complex scaffolds containing ~100 different proteins. Conceptually, kinetochores can be viewed as performing four distinct but highly integrated functions: 1) they bind centromeric chromatin at a specialized protein-DNA interface; 2) they build a dynamic microtubule-binding interface that is tightly linked to the centromere-binding interface; 3) they correct erroneous microtubule attachments; 4) they synchronize the progression of the cell cycle oscillator with the progression of the microtubule-kinetochore attachment process. In mammals, all four functions are essential, and their abrogation has untenable consequences for normal cell life. Conversely, their partial impairment has been implicated in chromosome instability and in the development of cancer and an array of genetic diseases. Our goal is to be able to map the kinetochore functions schematized above to the as yet largely uncharacterized architecture of the kinetochore and to unravel the elements of feedback control that allow their integration. By using a combination of structural and functional methods, we have made several recent important contributions to the field of kinetochore biology. In this application, we propose to take our efforts to a new level of complexity that will allow us to gain an integrated view of how kinetochores bind microtubules, how they correct improper attachment, and how they coordinate microtubule attachment with cell cycle progression. Our approach rests on strong experience in biochemical reconstitution and structural analysis, and is complemented by the introduction of methods to assess and model the dynamic responses of kinetochores to their variable environment.
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