Gennaro D'Urso, Ph.D.
Associate Professor of Cellular & Molecular Pharmacology
Description of Research
Dr. D’Urso’s research interest is in understanding the molecular mechanisms that control the initiation of DNA replication in eukaryotic cells. He is also interested in the checkpoint controls that respond to blocks to DNA replication initiation, and how these signaling pathways influence the decision to undergo cell cycle arrest or cell death. Using the fission yeast, Schizosaccharomyces pombe as a model system, the research team has identified genes that are required for DNA replication initiation. Most of the laboratory’s work has focused on the characterization of the genes encoding the catalytic subunit of DNA polymerase epsilon (Pol e) and its associated subunits. Cells defective for Pol ε arrest at the G1/S boundary, indicating this enzyme plays a critical role in the initiation step. Interestingly, the polymerization activity of this enzyme is not essential for cell viability, suggesting that Pol ε may have other roles, perhaps in the assembly of the replicative complex, that are not necessarily dependent on its ability to synthesize DNA. Studies in this laboratory on Pol ε have led to the discovery of a checkpoint control that is activated in response to defects in DNA replication initiation. The laboratory is currently continuing its efforts to identify proteins that are involved in the early steps of DNA synthesis and how these proteins may be involved in the activation of a checkpoint pathway that prevents premature entry into mitosis.
Moreover, considering that many of the features of these checkpoint pathways are evolutionarily conserved, Dr. D’Urso has begun studies to investigate the response of human cells to agents that block DNA replication initiation. Interestingly, tumor cells appear to behave differently than normal cells, triggering an apoptosis pathway, suggesting that blocking DNA replication might represent a powerful new approach to the treatment of cancer.
Finally, to better understand the relationship between different gene activities and the control of DNA replication checkpoints Dr. D’Urso is using a genomics approach to investigate the genes required for normal checkpoint function. These high-throughput yeast gene interaction studies should provide valuable information on the genetic networks that control DNA damage responses in all eukaryotic cells.
- Discovered Pol ε is required for initiation of DNA replication. These results were particularly important because Pol ε had earlier been shown to be non-essential for SV40 viral DNA replication, an extensively used model system of eukaryotic DNA replication. Recently, these early genetic studies were confirmed by biochemical analysis indicating that Pol ε assembly into the pre-Replicative Complex is one of the first events to occur prior to initiation and is dependent on CDK activation at the G1 to S phase cell cycle transition.
- Discovered the loss of the catalytic domains of this enzyme had no affect on cell viability in yeast. These observations have led to a new understanding of the role of Pol ε in DNA replication, and have suggested that Pol ε provides multiple functions in promoting DNA replication. The laboratory’s most recent data suggests that at least one of these functions is to facilitate assembly of the DNA replication initiation complex. These studies also led to the identification of a novel checkpoint responding to defects in DNA replication initiation.
Selected Cancer-Related Publications
Collaborating in the Multidisciplinary Research Program(s):