During the cell cycle, the cyclin-dependent kinases (CDKs) at the center of the cell cycle clock trigger a diverse set of events, including remodeling of the cell’s cytoskeleton. A number of internal surveillance pathways called checkpoint controls assess how key events are progressing and, if there is a hitch in some important process, they signal the clock to wait until the defect is corrected. In the past few years we have learned a lot about how the central clock works. However, several central questions remain concerning how the CDKs actually trigger many of the events, and how the checkpoint controls “know” whether things are proceeding according to plan.

We work with the tractable budding yeast as a model system, allowing us to make rapid progress on complex problems. One focus in the lab concerns a checkpoint pathway called the morphogenesis checkpoint, which monitors cytoskeletal polarization and bud formation, and inhibits G2 CDK activation if environmental stresses affect these processes. We are trying to understand how information about the cytoskeleton and cell shape is sensed and transmitted to the CDKs. A second focus concerns cell polarity, which is switched on by G1 CDKs and switched off by G2 CDKs in yeast. We would like to understand how global CDK activation makes cells develop (or dismantle) an asymmetric cytoskeleton. Because the genes and processes we study are highly conserved, we anticipate that learning the answers to fundamental questions in yeast will be relevant and informative for a wide range of organisms.

Theesfeld, C.L., Zyla, T.R., Bardes, E.S., and D.J. Lew.  A monitor for bud emergence in the yeast morphogenesis checkpoint.  Mol Biol Cell, 14:3280-3291. (2003).

Irazoqui, J.E., Gladfelter, A.S., and Lew, D.J.  Scaffold-mediated symmetry breaking by Cdc42p.  Nature Cell Biology, 5:1062-1070 (2003).

Lew, D.J.  The Morphogenesis Checkpoint.  Curr. Opin. Cell Biol., 15: 648-653. (2003).

Irazoqui, J.E. and Lew, D.J. Polarity establishment in yeast.  J. Cell Sci. 117, 2169-2171 (2004).

McNulty, J.J., and Lew, D.J. Swe1p responds to cytoskeletal perturbation, not bud size, in S. cerevisiae.  Current Biology 15: 2190-2198 (2005).

Irazoqui, J.E., Howell, A.S., Theesfeld, C.L., and Lew,D.J.  Opposing roles for actin in Cdc42p polarization.  Mol. Biol. Cell 16: 1296-1304 (2005).

Gladfelter, A.S., Kozubowski, L., Zyla, T.R., and Lew, D.J.  Interplay between septin organization, cell cycle and cell shape in yeast.  J. Cell Sci.  118: 1617-1628 (2005).

Keaton, M., and Lew, D.J.  The Morphogenesis Checkpoint: Progress and Controversy. Curr. Opin. Microbiol. 9: 540-546. (2006).

Keaton, M., Bardes, E.S.G., Marquitz, A.R., Freel, C.D., Zyla, T.R., Rudolph, J., and Lew, D.J. Differential susceptibility of S and M phase cyclin/CDK complexes to inhibitory tyrosine  phosphorylation in yeast.  Current Biology 17: 1181-1189 (2007).

Tong, Z., Gao, X-G., Howell, A., Bose, I., Lew, D.J., and Bi, E.  Adjacent positioning of cellular structures enabled by a Cdc42 GAP mediated zone of inhibition.  J. Cell Biol. 7: 1375-1384 (2007).

Lew, D.J., Burke, D.J., and Dutta, A.  The immortal strand hypothesis: how could it work?  Cell 133: 21-23 (2008).

Keaton, M., Szkotnicki, L., Marquitz, A.R., Harrison, J.C., Zyla, T., and Lew, D.J. Nucleocytoplasmic shuttling of G2/M regulators in yeast.  Mol. Biol. Cell 19: 4006-4018 (2008).

Szkotnicki, L., Crutchley, J., Zyla, T., Bardes, E.S.G., and Lew, D.J. The checkpoint kinase Hsl1p is activated by Elm1p-dependent phosphorylation. Mol. Biol. Cell 19: 4675-4686 (2008).

Kozubowski, L., Saito, K., Johnson, J.M., Howell, A.H., Zyla, T., and Lew, D.J.  Symmetry breaking polarization driven by a GEF-PAK complex. Current Biology 18: 1719-1726 (2008).

Crutchley, J., King, K., Keaton, M.A., Szkotnicki, L., Orlando, D., Zyla, T.R., Bardes, E.S.G., and Lew, D.J.  Molecular Dissection of the Checkpoint Kinase Hsl1p. Mol. Biol. Cell 20: 1926-1936 (2009).