Causes and consequences of aneuploidy.

For the building of an organism, it is essential that cell division occurs in a precise and orderly manner. Deciphering the regulatory networks that ensure accurate segregation of the genetic material is thus vital to understanding both normal cell division and abnormal cell division that leads to cancer and birth defects. My laboratory investigates the controls that ensure that chromosome segregation occurs accurately and that the process is orchestrated with other cellular events. In particular, our work determined the role of the protein phosphatase Cdc14 in the final stages of the eukaryotic cell cycle, called exit from mitosis. During exit from mitosis, cells complete the chromosome segregation phase and get ready for the next duplication phase. We showed that the protein phosphatase Cdc14 is a key trigger of this transition and that its activation during chromosome segregation is essential for exit from mitosis to occur. Furthermore, we elucidated the intricate regulation of Cdc14 by nucleolar sequestration. This work not only served as a paradigm as to how the regulation of the subcellular localization of a protein controls a key cell cycle transition but also shed light onto how exit from mitosis is coordinated with other cellular events such as chromosome segregation and mitotic spindle function. We also investigate what happens to yeast cells that, defying the odds, acquired extra chromosomes and hence are aneuploid. We discovered a set of phenotypes common to aneuploid cells that are independent of the chromosomal identity. These phenotypes include a delay in cell cycle progression, a transcriptional signature and effects on cellular homeostasis. The characterization of these cells as well as initial studies on aneuploid mammalian cells will be presented.