Reconstitution and Dissection of Chromosome Segregation

Abstract

From a broad scientific perspective, this project addresses a central question in biology that has fascinated investigators since the time of Gregor Mendel and his pea plants that we all learned about in high school: What physical processes drive chromosome inheritance? Chromosomes are segregated to ‘daughter cells’ during cell division, an exquisitely orchestrated event that requires many specialized cellular structures and regulatory components. Errors in chromosome segregation are genetic catastrophes in which one entire chromosome will be either gained or lost in the resulting ‘daughter’ cells. Further, these errors are instantly ‘set in stone’, because after cell division has completed there is no way for the cell to correct these genetic imbalances. Our proposed studies are needed to gain a molecular understanding of the mechanisms that drive human inheritance and enable healthy cells to faithfully guard the integrity of the genome. We are also keenly aware that progress we make will illuminate cellular pathways and molecular components that fail when chromosome segregation errors arise in the course of human disease (e.g. in Down syndrome and in most forms of cancer). Our proposal is to reconstruct chromosome segregation, literally joining the two most important structures: the chromosomes and the cellular cables, called ‘microtubules’, which attach to the chromosomes and drive their movements into the daughter cells. To accomplish this goal we will combine cutting edge multidisciplinary approaches that will achieve more together than the simple sum of their parts. Specifically, we will use state-of-the-art cellular manipulations and proven biochemical strategies to build functional synthetic chromosome ‘templates’—for which Dr. Black is a leader. With our highly advanced biophysical approaches and force-generating ‘laser tweezers’ — for which Dr. Grishchuk is an expert, we will interrogate the reconstructed individual chromosome connections. Thus, our work will bring to the cell division field the ability to dissect chromosome-microtubule attachments at a deeply mechanistic level, breaking through the barriers that have until now held our field back. During the grant period we will answer several pressing questions for how specific molecular components drive chromosome-microtubule attachments, while building a fertile ground for future studies that promise to lead to a quantum leap in our understanding of chromosome inheritance.

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