ANALYSIS AND CONTROL OF CHROMOSOME MOVEMENT

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The goal is to understand precise chromosome movement and the accurate distribution of chromosomes to the daughter cells in mitosis and meiosis. Errors in distribution can lead to cancer and to Down syndrome and other chromosome disorders in humans. How cells avoid errors is the subject of this project. Mechanical tension from mitotic forces is the key. Early in mitosis, chromosomes move to a position quite precisely midway between the spindle poles. Pushing and pulling motors regulated by tension may be responsible for this movement. The motors and their regulation will be characterized in materials that should reveal their action very clearly. The role of tension will be tested directly by pulling on chromosomes with a micromanipulation needle to increase or decrease the tension. The forces that produce chromosome movement will be measured in absolute units. These properties of living cells will be compared with expectations from the currently favored model for precise chromosome movement. The common errors in chromosome distribution are of two sorts, and tension is involved in avoiding both of them. Avoiding errors of the first sort depends on an anchorage of chromosomes to the spindle that is sensitive to tension. The source of the anchorage will be sought and its sensitivity to tension will be tested by micromanipulation. Errors of the second sort are avoided by a checkpoint that detects when tension is absent. Tension- sensitive protein phosphorylation may be the signal to the checkpoint. The biochemical activity that is sensitive to tension will be sought. A chromosomal kinase activity will be tested first, by seeing if it is affected when tension is altered experimentally. Development of an in vitro system in which mechanical and biochemical manipulations can be combined is proposed, with the aim of connecting mitotic forces with the biochemistry of the checkpoint.