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Finding Cures. Saving Children.
Kitagawa R: Characterization of the molecular link between the DNA damage checkpoint and mitotic arrest
In the past several years, DNA damage checkpoint proteins in C. elegans have been identified, and the functions of these proteins in germline cells have been partially elucidated. However, the components of downstream events of the pathway have not been identified. To elucidate the molecular mechanism(s) of the DNA damage checkpoint pathway in C. elegans, we must identify the molecular targets of the pathway.
In budding yeast, the anaphase-promoting complex (APC) associated with Cdc20 targets the mitotic regulator Pds1, and degradation of Pds1 triggers the onset of anaphase. The mitotic spindle checkpoint complex inhibits the APC activity via binding to Cdc20. This inhibition stabilizes Pds1 and delays the onset of anaphase. In the presence of DNA damage, the checkpoint kinases Mec1 and Rad53 mediate Pds1 phosphorylation, a finding that suggests that Pds1 is involved not only in the mitotic spindle checkpoint pathway, but also in the DNA damage checkpoint pathway (Cohen-Fix and Koshland, Proc Natl. Acad. Sci. U S A. 1997). I identified a novel C. elegans protein IFY-1, which interacts with C. elegans Cdc20 (FZY-1) and separase (SEP-1). IFY-1 is accumulated in one-cell–arrested embryos of an APC-deficient strain. RNA interference–induced reduction of ify-1 expression causes an embryonic-lethal phenotype. These findings suggest that IFY-1 and Pds1 share a common function in the mitotic cell cycle. It would be interesting to test whether IFY-1 is a target in the DNA damage checkpoint pathway. This research focus will be initiated by investigating the stability of IFY-1 in DNA damage checkpoint–deficient strains.
Although the worm model is one of the most powerful tools for identifying components involved in signaling pathways, it might have some limitations in regard to determining their functional significance in mammals because of the difference in the complexity of the two organisms. Therefore, it would be appropriate to analyze the function of mouse homologs in mouse models. I will generate a knock-out or knock-in mouse, which will be chosen from mutants identified by the genetic screens mentioned above.
