Cell cycle checkpoints, chromosome stability and the progression of cancer.

During the evolution of normal cells into cancer cells, the occurrence of multiple mutations results in genetic instability. Mutations in DNA repair genes such as those of mismatch and excision repair predispose the carriers of these mutations to cancer by increasing the level of genomic instability. A variety of chromosome aberrations, such as abnormal ploidy, whole chromosome loss or chromosome amplification are commonly observed in cancer cells. From one cell division to the next, mammalian cells pass through an organized series of controlled events referred to as the cell cycle. In order to pursue an ordered series of molecular events, the initiation of an event during cell cycle progression is dependent on the successful completion of an earlier event. The cell cycle is divided into two major phases, namely, M(mitotic) phase and interphase. Interphase can be further divided into three distinct phases termed G1 (gap 1), S(DNA synthesis) and G2(gap2) phases (Fig. 1). Along with the machinery that promotes cell cycle progression, cells are also equipped with cell cycle checkpoints that ensure correct ordering of events in the cell cycle. The idea of "the cell cycle checkpoint" was first introduced by Hartwell and Weinert (1989) as "the arrest of a cell at a particular phase of the cycle due to a lack of appropriate signals for cell cycle progression". Until the checkpoint machinery receives the appropriate signal, the cell will not be allowed to make transition from one phase of the cell cycle to the next. Thus, the major role of checkpoint control is to minimize somatic genetic alterations and/or events affecting cellular survival. When one or more components of a cell cycle checkpoint are mutated, the chances of genetic instability during one round of the cell cycle increase accordingly with consequent acceleration of cellular evolution from the normal to the cancerous state. Therefore, mutations in checkpoint controls may predispose cells to cancer by causing genomic instability. In this review, I will focus on the potential roles of cell cycle checkpoints in the progression of malignancy.