Start To fight cancer

The recent completion of the Saccharomyces pombe genome revealed an impressive number of fission yeast genes with human homologs implicated in cancers. Interestingly, lots of of these genes have known or implied functions in DNA replication in yeast. Current proof suggests that multiple pathways of control of eukaryotic DNA replication can be disrupted to lead to genome instability & predisposition to cancer. Thus, deregulation of CDK activity, weakened origin firing, changes in the timing of firing, loss of control in the order of S phase & M phase, & inability to limit replication to one time per cell cycle are all mechanisms that may lead to changes in chromosome structure & gene function. In addition, defects in the checkpoint response to replication blocks, & the inability to reply appropriately to stalled replication forks, also contribute to genome instability. Ultimately, the gain or loss of genetic knowledge may lead to inappropriate expression of proto-oncogenes or loss of tumor-suppressor function.

When the normal timing of origin firing is disrupted, cells are susceptible to deregulated cell cycle progression. This might result either through refiring of origins in a single cell cycle, or through firing late origins of replication under conditions where they are normally prevented from firing. Treatment of Saccharomyces cerevisiae cells with the antitumor drug adozelesin changes the normal pattern of replication such that active replication forks are cations of mammalian chromosomes also may fine-tune replication timing of a specific sequence. Conversely, uncontrolled cell proliferation may lead to deregulation of replication timing. This is observed both in checkpoint mutants in S. pombe & in human cancers. Thus, disruption of the timing & coordination of replication is pathwaytoward genome instability.