Ongoing Research Highlights

We have three main areas of research: (i) the role(s) of the RZZ complex in mitotic checkpoint regulation and (ii) the role of the mitotic checkpoint in mitotic catastrophe (iii) cell cycle kinases Wee1 and Myt1 synthetic lethality in breast cancer.
(i) The RZZ complex consists of three proteins, Rod, Zw10 and Zwilch. They are kinetochore proteins that recruit the microtubule motor, dynein/dynactin, to kinetochores but were found to be also essential for the mitotic checkpoint. The RZZ complex is essential for the recruitment of the mitotic checkpoint effector Mad2 to kinetochores. The exact mechanism is still unknown. We are using molecular, biochemical and cell biological approaches to study the structure and function of the mitotic checkpoint apparatus in order to understand the underlying mechanism.
(ii) Mitotic catastrophe is a cell death phenomenon that has been observed, however, there is not a molecular marker and the mechanism of action is not known. We are following up on the findings that genotoxic treatments of cancer cells often result in checkpoint adaptation and ultimately mitotic catastrophe. We have observed that prolonged mitotic arrest and centromere fragmentation often accompany mitotic catastrophe. We are examining the role of the mitotic checkpoint in this cell death process.
(iii) Wee1 and Myt1 are cell cycle kinases that mediate inhibitory Cdk1 phosphorylation. In addition to being important for regulating the G2/M checkpoint, they are also essential for inhibiting Cdk1 activity at the end of mitosis. MK-1775 is a small molecule inhibitor of Wee1 kinase activity and is currently undergoing Phase I/II clinical trial for multiple cancers. We have identified the Myt1 kinase as a resistance factor for MK-1775 in breast cancers. We are examining the mechanism of Myt1 function in mediating MK-1775 resistance.