MECHANISM OF A DNA DAMAGE INDUCED CELL CYCLE CHECKPOINT

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The goal of this project is to elucidate how DNA damage arrests the cell cycle before mitosis in Schizosaccharomyces pombe and to investigate the role of the gene rad3, a homolog of the human ataxia telangiectasia gene (ATM), in this process. In all studied post-embryonic cells, DNA damage during G2 leads to arrest of the cell cycle at the 02/M boundary. This checkpoint control is thought to require the product of AIM gene or its homologs and to function via the inhibition of the mitotic Cdk/cyclin complexes. In S. pombe there are ten genes known to be required for the DNA damage checkpoint, seven of which, including rad3, are also required for the DNA synthesis checkpoint. However, the DNA damage and DNA synthesis checkpoints cause cell cycle arrest by different mechanisms. DNA synthesis- induced cell cycle arrest is caused by the inhibitory phosphorylation on Y15 of Cdc2, while the mechanism of DNA damage-induced cell cycle arrest is distinct and uncharacterized. Thus, there are currently two major questions regarding the S. pombe DNA damage checkpoint. How is the cell cycle arrested at the 02/M boundary in response to DNA damage? And, what is the role of the rad genes that are required for both the DNA damage and DNA synthesis checkpoint pathways?