W. Matthew Michael
Replication Checkpoint Signaling Complex (RCSC)
My lab is interested in the mechanisms by which cell cycle checkpoints prevent cell division when chromosomes are either damaged or in the process of being replicated. Loss of checkpoint function allows cells to enter patterns of unrestrained growth. This can result in neoplastic transformation, and, ultimately, tumor formation. Therefore, the interests of my lab are highly relevant to cancer biology and are of critical importance to the design of more specific and effective anti-cancer drugs.
Checkpoints can be thought of as signal transduction pathways that initiate on damaged or replicating chromosomes and culminate in alteration of the activity of important cell cycle regulators. An interesting problem in cell biology is the nature of the signal that activates checkpoint pathways. We have recently found that, for the replication checkpoint, synthesis of the RNA portion of the primer (initiator RNA or iRNA) during replication is sufficient to activate the checkpoint. A top priority for future work will be to follow up on this discovery in order to understand how iRNA synthesis activates the known components of checkpoint signaling pathways.
Additionally, we will explore how these pathways, once they are activated, serve to arrest the cell cycle. The focus here is on Wee1, a negative regulator of mitosis. We have previously shown that Wee1 proteolysis is negatively-regulated by checkpoint activation. This regulation appears to be independent of known checkpoint proteins, therefore, identification and characterization of Wee1 regulators promises to provide new insight into how checkpoints regulate the cell cycle.
Finally, we will combine biochemistry and proteomics with a novel expression cloning system and clever assays in order to identify and characterize new checkpoint proteins. The long-term goal of these studies is to generate a molecular map for how checkpoints are activated and for how they work. Once such information is available we will focus on small compound activation of checkpoint pathways so that drugs can be found that mimic the behavior of checkpoint proteins. These compounds could potentially be useful in cancer treatment and prevention.
The lab also has interests in the mechanisms and regulation of chromosomal replication during S phase, as well as in the basic principles of nucleo-cytoplasmic transport through nuclear pore complexes.