About MeChromosome segregation, kinetochore structure and assembly, mitotic checkpoint control, and chromosome cohesion
In my laboratory, research is centered
on the mechanism of cell cycle control and particularly the regulation of accurate chromosome segregation during mitosis. The mitotic checkpoint is a failsafe
mechanism by which the cell prevents premature anaphase and ensures accurate chromosome segregation. The relevance
this line of basic research to cancer is established in the demonstrated importance of chromosome fidelity during cell division to carcinogenesis. Somatic mutations of mitotic checkpoint genes have been identified and postulated to be important for the chromosome instability phenotype in colorectal cancers. By investigating the molecular mechanism of the mitotic checkpoint, we can better evaluate these genes as potential cancer drug targets as well as contributing to the basic understanding of cancer.
We are currently examining the mechanisms by which mitotic checkpoint proteins monitor kinetochore: microtubule attachments to ensure that cells with misaligned chromosomes are provided extra time to establish proper connections to the spindle. hZw10 and hROD
are kinetochore proteins that recruit dynein/dynactin to kinetochores but were found to be also essential for the mitotic checkpoint. We propose that hZw10 and hROD
attachments mediated by dynein to the checkpoint.
Research training is available for undergraduate summer students, undergraduate honors research project students, undergraduate co-op students, graduate students and post-doctoral fellows. Individuals interested in graduate work in Oncology in my laboratory should have a strong background in molecular biology, biochemistry and/or cell biology, since research projects typically involve the use of platform technologies from these disciplines. Funding for students and fellows is available through application to competitive agencies (e.g., AHFMR, CIHR, NSERC, NCIC, ACB) or from operating grants to the Chan research program.
My main research interest is to understand the molecular mechanisms of mitotic checkpoint control in mammalian cells. We propose to examine the mechanism of action of three recently identified checkpoint proteins, roughdeal
), hZw10, and hMPS1. hRod
and hZw10 function in two ways during mitosis. Firstly, hRod
and hZw10 specify the assembly of the microtubule (MT) motor dynein/dynactin to kinetochores during mitosis. Secondly, hRod
and hZw10 are essential components of the mitotic checkpoint and they interact with the checkpoint kinase hBUB1. We propose that hRod
/hZw10 and hBUB1 may be part of a mechanosensory complex that monitors kinetochore:MT
interactions mediated by the dynein/dynactin complex.
Microtubule, mitosis, drug, inhibitor, cell cycle