A fission yeast homologue of the human uracil-DNA-glycosylase and their roles in causing DNA damage after overexpression

A functional homologue (ung1) of the human uracil-DNA-glycosylase (UNG) gene was characterized from fission yeast (Schizosaccharomyces pombe). The ung1 gene is highly conserved and encodes a protein with uracil-DNA-glycosylase activity similar to human UNG. The Ung1 protein localizes predominantly to the nucleus, suggesting that it is more similar to the nuclear form (UNG2) than the mitochondrial form (UNG1) of human UNG. Even though deletion of ung1 does not cause any obvious defects, overexpression of ung1 increases the mutation frequency. Overexpression of ung1 or human UNG2 induces a DNA checkpoint-dependent cell cycle delay and causes cell death which is enhanced when the checkpoints are inactive. In addition, the steady-state level of AP (apurinic/apyrimidinic) sites increases after ung1 overexpression, indicating that AP sites are likely to be the DNA damage caused by overexpression. Analysis of mutant ung indicates that catalytic activity is not required for the effects of overexpression, but that binding of Ung1 or UNG2 to AP sites may be important.