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Accurate cell division is essential for the growth and development of all organisms, and because of this, many critical steps in the cell cycle are controlled by overlapping or redundant mechanisms. The cell cycle is regulated at three levels–transcription, protein degradation, and phosphorylation–all of which are important to order cell-cycle events. Regulated transcription of genes with functions in the cell cycle ensures that proteins are expressed when their functions are needed, or immediately before. Protein degradation by the ubiquitin proteasome system abruptly eliminates the activities of regulators after their functions are complete. Finally, phosphorylation by cell cycle-regulatory kinases fine-tunes the activity and/or degradation of hundreds of proteins. Our goal is to understand how these different modes of regulation are integrated to generate a robust control network. A better understanding of this network will enable us to identify regulatory steps that can be targeted to inhibit proliferation and develop more effective cancer therapies.

Phosphoregulation of the cell-cycle transcription factor network

Progression through the cell cycle is driven by a carefully orchestrated and precisely ordered gene expression program. This gene expression pattern is established by a network of conserved transcription factors (TFs), many of which are misregulated in cancer cells. The activities of these TFs are regulated by cyclin-dependent kinase (CDK), resulting in carefully timed expression of cell cycle-regulated genes. Our lab studies how CDK phosphorylation controls the activities of TFs that function late in the cell cycle (Landry et al, EMBO J, 2014).

Phosphorylation by CDK also provides a layer of regulation that can rapidly respond to extracellular cues. We are studying how cell cycle-regulated phosphorylation is controlled in response to environmental stress. the role of the stress-activated phosphatase calcineurin in removing CDK-catalyzed phosphorylations in response to environmental stress. In collaboration with Martha Cyert's lab, we discovered that the balance of positive and negative phosphorylation on Hcm1 is disrupted by calcineurin in response to stress signals, which leads to rapid Hcm1 inactivation (Arsenault et al, Mol Biol Cell, 2015). More recently we discovered that calcineurin inactivates multiple TFs in the cell cycle network, in part through crosstalk to the stress-activated MAPK Hog1/p38 (Leech, Flynn, et al PLoS Genet, 2020). These projects are complemented by work in human cells aimed at understanding the regulation of oncogenic transcription factors that are core components of the cell-cycle network.

Cell-cycle regulation by the ubiquitin proteasome system

Protein degradation via the ubiquitin-proteasome system is essential for cells to grow and divide. Consistent with this role, numerous ubiquitin ligases (E3s) that target proteins to the proteasome for degradation, as well as deubiquitinating enzymes (DUBs) that antagonize E3 function, are mutated in cancer cells. However, the targets of most of these enzymes remain unknown. We use budding yeast as a model system to determine how conserved E3s and DUBs recognize and select their substrates, and to develop proteome-wide approaches to identify targets of these critical enzymes (Benanti et al, Nat Cell Biol, 2007, Mapa et al, Mol Biol Cell, 2018). Our work led to the unexpected discovery that two cell cycle-regulatory E3s redundantly ubiquitinate key cell-cycle proteins  (Landry et al, PLoS Genet, 2012). Current projects aim to expand upon these discoveries and to identify DUBs that are part of the cell cycle control network.

Coordination of chromosome structure and the cell cycle

Before a cell divides, chromosomes are disentangled from one another and condensed into highly compacted structures that facilitate sister chromatid separation by the mitotic spindle. After mitosis is complete, this compaction must be reversed, to make the genome accessible for replication and transcription during interphase. In the course of our screens to identify how cell-cycle proteins are regulated, we discovered a mechanism that contributes to the reversal of chromosome condensation after mitosis. The condensin complex is one of the primary mediators of chromosome condensation in all eukaryotes. We found that expression of one subunit of condensin, yeast CapG (Ycg1), is cell cycle-regulated and limiting for complex function (Doughty et al, PLoS Genet, 2016). Ycg1 is normally downregulated after mitosis, and cells that constitutively express Ycg1 exhibit a delay in progressing through the cell cycle. Current projects aim to understand how condensin complexes are regulated throughout the cell cycle in both yeast and human cells.