Errors in chromosome transmission alter the balance of tumour suppressor and tumour promoter genes. This facilitates subsequent changes in genome composition in the ensuing cell divisions, ultimately leading to transformation and cancer. Cell cycle controls ensure that a cell does not segregate its replicated genomes until a number of criteria are fulfilled. Not only must cells have undergone the appropriate degree of growth to justify division and receive the right external cues, but the genome must also be intact and any damage that has occurred since DNA replication must have been repaired. Mitotic checkpoint networks within mitosis then ensure that the splitting of the chromosomes into two identical chromatids does not happen until all of the chromosomes have attached to both spindle poles and cells do not leave mitosis until all stages of mitosis have been done correctly.
Lessons from yeast
The ability to manipulate genes at will in a simple organism, whose primary purpose is to divide, is enabling us to explore the finer points of the pathways that co-ordinate a successful cell division. This information informs studies in higher systems that, in turn, raise models that can be most readily tested in yeast. This iterative cycle of comparative studies ensures that great strides are being made in understanding the molecular basis of cell division.
Cell cycle control in fission yeast
The molecules that regulate progression through the cell division cycle are essentially the same in all eukaryotes from yeast to man. Yeast are single, free living fungi whose prime objective, in the right conditions, is to grow and divide. They have a short cell division cycle, are genetically malleable, have good cytology and are amenable to study by biochemistry. Studies of progression through the relatively simple yeast cell division cycle have therefore often paved the way for the study of more complex processes in human cells. Many of the molecules that regulate cell division in humans were first identified by studies in simple model systems such as yeast, fruit flies or frog eggs. We study cell division in fission yeast.
Regulating commitment to mitosis from the spindle pole
Commitment to mitosis is triggered by activation of Cdk1-Cyclin B. During interphase Wee1 related kinases phosphorylate the catalytic, Cdk1 subunit to inhibit the complex. This phosphate is removed by Cdc25 phosphatases to promote mitotic entry. Cdk1-Cyclin B activation promotes a positive feedback loop that boosts Cdc25 and inhibits Wee1 activity. This feedback loop includes polo kinase. The spindle pole component Cut12 associates with polo kinase, modulates its activity and can be mutated to promote mitosis in cells that lack Cdc25. This suggests that commitment to mitosis is promoted by events on the spindle pole.
MPF activation triggers downstream kinases
Although MPF directly activates a limited number of molecules that mediate chromosome segregation, the principle mechanism by which it promotes mitosis is by activating a set of downstream kinases that includes kinases related to Polo, aurora, NIMA and Mps1. Activation of these kinases promotes the formation of the condensation of chromosomes, the attachment of the chromosomes to the spindle and the formation of the polo, aurora and NIMA kinase.