Mechanisms ensuring sister kinetochore bi-orientation on the mitotic spindle

To make a human body from a single cell (a fertilized egg), an enormous number of cell divisions must take place. Human cells store their genetic information within 46 structures called chromosomes. To maintain this genetic information, all chromosomes must be precisely copied and each daughter cell must receive one copy of each chromosome upon each cell division. Failure in this process may cause cancers and genetic abnormalities. The aim of our research project is to clarify the fundamental mechanisms by which all chromosomes are properly inherited by daughter cells. Because such mechanisms are similar in yeast and human cells, we will use yeast as our research material. Yeast has a number of advantages over human cells for our study, for instance the roles of all proteins in the yeast cell have been systematically studied, many mutants have been identified and chromosomes can be easily engineered to suit our experiments. By using microscopy and biochemical methods, we will study the mechanisms of chromosome separation during cell divisions. Revelation of these fundamental mechanisms will help us to understand how various human diseases develop.

To maintain their genetic integrity, eukaryotic cells must segregate their chromosomes properly to opposite spindle poles during mitosis. This process mainly depends on the forces generated by microtubules that attach to kinetochores. For proper chromosome segregation, sister kinetochores must be captured by spindle microtubules extending from the opposite spindle poles, prior to anaphase onset; this state is called sister kinetochore bi-orientation. Using budding yeast as a model organism, we will study the molecular mechanisms that ensure sister kinetochore bi-orientation on the mitotic spindle. With live cell imaging and biochemical approaches, we will address how re-orientation of kinetochore-spindle pole connections proceeds and facilitates bi-orientation, and investigate how re-orientation is regulated by two mitotic kinases Aurora B (Ipl1 in yeast) and Mps1, major regulators for bi-orientation. Our research should contribute to understanding mechanisms for bi-orientation in human cells because basic mechanisms for chromosome segregation are well conserved from yeast to humans.