Current Research

Our laboratory works on cell biology topics in two interrelated areas: cytoskeletal dynamics and the control of genome stability. We take a range of approaches including genetics, functional genomics, biochemistry and live cell imaging. There are ongoing projects using both yeast and animal cell systems.

Our work on cytoskeletal dynamics has primarily focused on asymmetric cell division: how the mitotic spindle senses polarity cues at the cell cortex, and how the actin and microtubule cytoskeletal systems are integrated to correctly position mitotic spindles. We seek to understand how these protein complexes generate coordinated movement through biochemical and imaging approaches. Our group recently found that the positioning of mitotic spindles requires actin a novel actin assembly system mediated by formin proteins. Formins nucleate the assembly of actin filaments and the filaments assembled by formins are linear unlike the branched filaments assembled by the other known actin nucleator: the Arp2/3 complex. Formins are regulated by Rho-type GTPases. This suggests a simple model of how differently shaped actin structures are formed in cells: different nucleators initiate differently shaped “building blocks” that are assembled into different structures. Our work in this area is assisted by a crystal structure of the formin actin nucleation domain, solved in collaboration with Mike Eck's group. Current related projects in the laboratory address: (1) the molecular mechanism of formins in living cells using quantitative imaging methods, (2) the mechanisms to control formin activity in cells, and (3) the cell cycle control of Rho-GTPases.

A second area in the laboratory addresses mitotic mechanisms promoting genome stability and preventing cancer. We have recently found that inhibiting cytokinesis, generating tetraploid cells promotes tumorigenesis, using a mouse mammary epithelial transplant system. This is the first direct test of an almost 100 year-old hypothesis. One mechanism by which tetraploid cells may promote tumorigenesis is by chaotic mitoses induced by extra centrosomes. Extra centosomes are a common feature of cancer cells. Cells have an adaptive mechanism to organize extra centrosomes to prevent chaotic mitoses. Genome-wide siRNA screens are in progress to define these adaptive mechanisms. Finally, we recently found that loss of certain genes results in a genetic phenomenon that we call ploidy-specific lethality: the genes are not essential in cells with a normal complement of chromsomes but become essential when ploidy is increased. The ploidy-specific requirement for certain gene products could have implications for a wide variety of biological processes and may provide a new strategy to identify targets for anti-tumor drug development. How the mechanism of mitosis is altered when ploidy is increased is being characterized by functional genomic approaches in yeast and animal cells.