Microtubule Dynamics and Mitotic Mechanism

Harvard Medical School, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Summary. When cells divide they build a transient structure called the mitotic spindle to separate their chromosomes into two equal groups. Spindle assembly is a fundamental and fascinating process. We will study the molecules required to build mitotic spindles, and how they generate structures and forces within spindles. Blocking spindle assembly is an effective way of killing cancer cells, and understanding basic mechanisms of spindle assembly will reveal targets for more effective anti-cancer drugs. In the last grant period, we discovered that an unusual molecule called poly(ADP-ribose) is an essential building block of spindles, and we hypothesize that it may be part of a mysterious "spindle matrix" that helps physically organize spindles. We will look for proteins that bind to this molecule, and determine how it contributes to structures and forces within the spindle. The most studied components of spindles are microtubules, long filaments made of the protein tubulin, which grow and shrink rapidly and generate force on chromosomes. We will investigate the biochemical reactions that create new microtubules in the spindle. We will also use new microscopy methods to visualize how microtubules move within the spindle, and mathematical models to understand how the creation, movement and loss of microtubules generates the characteristic size and shape of spindles. Relevance Our studies will address major unresolved questions about how spindles self-organize to generate a stereotyped structure that nevertheless adjusts itself depending on circumstances, and how they perform their essential biological functions. These discoveries will have immediate relevance to the development of novel cancer drugs.