Cell division is accomplished through a series of events that ultimately lead to the production of two daughter cells that are genetically identical. This series of events comprise what is called the cell cycle, during which all of the chromosomes in the cell are duplicated and then equally divided between the two daughters. It is crucial that each step be completed before the next step occurs to ensure that each daughter cell receives a full complement of normal genes. Genetic or environmental insults to the cell can delay the completion of steps that are essential for cell division. However, cells have evolved surveillance mechanisms called “checkpoints” that halt progression of the cell cycle until each step is completed. Checkpoints consist of sensors that detect whether a cell cycle process has been successfully completed, and effectors that relay signals from the sensor to the cell cycle machinery and halt its progress. Without such cell cycle checkpoints, genetic errors accumulate and can cause cell death or diseases such as cancer.

In the budding yeast Saccharomyces cerevisiae, cytokinesis occurs at the mother-bud neck, and cells must move the spindle into the neck before cell division. The major mechanism for spindle movement is dynein/dynactin-dependent sliding of astral microtubules along the bud cortex. Dynein is a microtubule motor whose function is regulated by a protein complex called dynactin. In cells lacking functional dynein or dynactin, spindle movement into the neck is delayed and cytokinesis is also delayed until the spindle moves into the neck via a backup mechanism . We previously found that dynein/dynactin mutants lacking a microtubule binding protein, Bim1p (also known as Yeb1p), frequently divided without moving spindles into the neck, providing strong evidence for the existence of a cell cycle checkpoint that monitors spindle position and that fails in these mutants.

Recent papers from Angelika Amon’s and Elmar Schiebel’s labs have suggested a model for how the spindle position checkpoint might work. A small G-protein called Tem1p is required for mitotic exit and acts upstream of a network of signalling proteins. Like most small G-proteins, the GTP-bound form of Tem1p is thought to be active. Tem1p and its putative inhibitor, Bub2p/Bfa1p (a presumed GTPase activating protein or GAP), are both localized to the end of the spindle destined to move into the bud. Lte1p, the putative activator of Tem1p (a presumed guanine-nucleotide exchange factor or GEF), is polarized to the bud. In the model proposed, Bub2p/Bfa1p is responsible for keeping Tem1p in an inactive state on the end of the spindle while it is in the mother. Subsequent spindle movement into the neck is thought to promote exit from mitosis by allowing Lte1p in the bud access to Tem1p at the end of the spindle in the bud.

Although this model is attractive, it is clearly not the whole story. First, at normal temperatures, Lte1p is not necessary for mitotic exit and cytokinesis, suggesting that Tem1p is active enough to promote mitotic exit without Lte1p. However, Lte1p is required to activate Tem1p at low temperatures, presumably because the intrinsic activity of Tem1p reduced. Second, in some cases, cytokinesis and mitotic exit occur without spindle movement into the neck or interaction of the end of the spindle with the neck. These cases occur when Bub2p or Bfa1p are absent or when astral microtubules fail to penetrate the neck. These observations suggest a complementary model in which the presence of astral microtubules in the neck inhibits progression to mitotic exit, probably through Bub2p/Bfa1p activity. Loss of astral microtubules from the neck, due either to movement of the nucleus into the neck or microtubule instability, would then result in loss of Bub2p/Bfa1p activity and allow the cell to exit mitosis.

Many of the yeast proteins involved in the spindle position checkpoint and the regulation of cell division are conserved in higher organisms. However, little is known about how these homologues function and it is not known if a spindle position checkpoint exists in higher organisms. Finding how the checkpoint is regulated in yeast and, more generally, about how mitotic exit and cytokinesis are controlled in yeast and vertebrates could potentially help us understand developmental and disease processes governed by cell division control.