The mitotic kinase, Aurora-A (Aur-A), is important for accurate chromosome segregation. AurA is amplified or over expressed in most of the common cancers. Experimentally, forced over-expression of Aur-A results in aneuploidy, cellular transformation, and tumor formation in mice. New evidence suggests overexpression of Aur-A may override a DNA damage-induced G2 checkpoint arrest. Xenopus egg cycling extracts, which carry out many cell cycle events in vitro, are a convenient and powerful system to investigate the roles of Aur-A in DNA damage checkpoint control. In the proposed work, I will first determine the exact timing of AurA activation in relation to cdc2 activation and the G2tM transition in cycling extracts. I will then ask if DNA damage checkpoints, which block activation of cdc2, also inhibit Aur-A activation. If so, I will determine if this inhibition depends on p53. I will lastly test how the over-expression of AurA may override checkpoint arrest in mammalian somatic cells. These experiments will address the potential important role of Aur- A in proceeding into mitosis under both normal and checkpoint-arrested cell cycle. Studying the potential role of Aur-A in DNA damage checkpoint should provide new insights for understanding the underlying mechanisms for both tumorigenesis and resistance to DNA damage chemotherapy.
