Dr. Scott K. Davey

Scott K. Davey, Ph.D.

Email: sd13@queensu.ca
Office Phone: 613-533-6923
Fax: 613-533-6830

  • Associate Professor of Pathology & Molecular Medicine, Oncology, and Biochemistry
  • B.Sc., Ph.D., University of Western Ontario
Dr. Davey's Lab

Human Cell Cycle Checkpoint Control

DNA damage and cell cycle control are linked through signal transduction pathways termed checkpoints. These pathways sense various forms of DNA damage, and transduce a signal that transiently arrests cell cycle progression long enough to allow resolution of the damage. Defects in genes regulating this process are causative agents in various cancer syndromes, including ataxia telangiectasia (Atm), Li-Fraumeni syndrome (p53 and Chk2), Bloom's syndrome (Blm), Nijmegen breakage syndrome (Nbs1), and hereditary breast and ovarian cancer (Brca1 and Brca2). In addition, transgenic mouse studies have shown that many other proteins that function in this pathway are essential for viability, including the Atm-related Atr, and the PCNA-like hRad1 and hHus1.

Our studies in this area focus on the hRad9 protein, which (along with hRad1 and hHus1) falls into the PCNA-like protein category. hRad9 forms a heterotrimeric complex with hRad1 and hHus1, called the "911" complex, that is loaded onto DNA at sites of damage. Depending on the type of damage, one of the Atm or Atr kinases independently localizes to these sites, and it is thought that together the 911 complex and Atm or Atr transduce the checkpoint signal. We have published a number of findings regarding the biochemical regulation of hRad9, including evidence that hRad9 is regulated in both a cell cycle-dependent, and in a DNA damage-dependent manner, by extensive phosphorylations near the C-terminus of the protein. We have also demonstrated that hRad9 localizes near PCNA and active sites of replication in S phase cells, and with H2AX to sites of DNA damage/repair in cells that have been exposed to ionizing radiation. We have also developed evidence supporting a direct interaction between hRad9 and another member of the DNA damage response pathway, TopBP1, suggesting a mechanism for signal transduction downstream of hRad9.

In addition to these biochemical analyses, we have been able to show defects in the cell cycle checkpoint response in cells that have attenuated hRad9 function. We have developed an interfering RNA (siRNA)-based system for reducing endogenous hRad9 and replacing it with exogenous mutant forms, so that we may study the specific effects of phosphorylation site mutants on hRad9 function, and on events downstream of hRad9.

Specific projects that are currently underway include:

  • Completion of our analysis of hRad9 phosphorylation, including identification of kinase(s) responsible for phosphorylation of hRad9
  • Determine how cells with compromised hRad9 respond to DNA damage, primarily using cells with compromized endogenous hRad9 in which we transiently expres hRad9 point mutants
  • Determine what downstream damage processing events are dependent on proper hRad9 structure and function
  • A collaborative assessment of hRad9 structure via X-ray crystallography.

(This work is funded by the Canadian Institutes of Health Research)

Selected Publications:

  1. Greer, D.A., B.D.A. Besley, K. Kennedy, and S. DAVEY (2003) "hRad9 binds double strand breaks is required for damage-dependent TopBP1 focus formation." Cancer Res 63, 4829-4835.
  2. St. Onge, R.P., B.D.A. Besley, J. Pelley, and S. DAVEY (2003) "A role for the phosphorylation of hRad9 in checkpoint signalling." J. Biol. Chem 278, 26620-26628.
  3. Lieberman, H.B., K.M. Hopkins, M. Nass, D. Demetrick, and S. DAVEY (1996) "A human homolog of the Schizosaccharomyces pombe rad9 checkpoint control gene." Proc. Natl. Acad. Sci. USA 93, 13890-13895.
  4. Walworth, N., S. DAVEY, and D. Beach (1993) "Fission yeast Chk1 protein kinase links the rad checkpoint pathway to cdc2." Nature 363, 368-371.

DNA Damage Response In Fission Yeast:

In addition to our studies of the checkpoint response in human cells, we have been using fission yeast as a model system to study the DNA damage response. Much of our early work focussed on the Uve1 protein, and it function and regulation. We continue in this line of work, taking advantage of the genetically tractable yeast system to study pathways that are both conserved in humans, and often defective in human tumour cells. We expect this work will lead to a better understanding of the DNA damage response in general, and ultimately to improvements in understanding and treating cancer that comes with a more detailed understanding of oncogenesis.

In general, our work in this area falls into three categories, which are aimed at: 1) Continuing our established research into the mechanisms of repair of oxidative DNA damage; 2) Continuing our established research into regulatory aspects of the DNA damage response; and 3) Initiating novel studies to maximally utilize the fission yeast model system in ways that might be of most direct relevance to cancer treatments. Ultimately, we will use information gained here to increase our understanding of DNA damage processing, and how this process works under normal circumstances. Using yeast genetics, we can simulate many of the defects commonly found in human cancer cells, and determine how such transformation leads to altered processing of damage, and to mutation accumulation. This work will shed light on this critical process in the maintenance of genomic stability.

Specific projects that are currently underway include:

  • Genetic characterization of the fission yeast base-excision repair pathway, expanding from our published work on Uve1, Apn2, and Nth1 to include Apn1 and Myh1.
  • Integration of BER genetics with NER and MMR pathways to determine how these pathways cooperate to repair damage caused by oxidizing agents.
  • A biochemical characterization of the repair of 8-oxoguanine.
  • Genetic and biochemical characterization of abnormal gene silencing in checkpoint deficient yeast.
  • Screening for additional genes which regulate genomic stability.

(This work is funded by the National Cancer Institute of Canada with funds from the Canadian Cancer Society Terry Fox Run)

Selected Publications:

  1. Fraser, J.L.A., E. Neill, and S. DAVEY. (2003) "Fission yeast Uve1 and Apn2 function in distinct oxidative damage repair pathways in vivo." DNA Repair 2, 1253-67.
  2. Kaur, B., J.L.A. Fraser, G.A. Freyer, S. DAVEY, and P.W. Doetsch. (1999) "A Uve1p-mediated mismatch repair pathway in Schizosaccharomyces pombe." Mol. Cell. Biol. 19, 4703-4710.
  3. Freyer, G.A., S. DAVEY, J.V. Ferrer, A.M. Martin, D. Beach, and P.W. Doetsch (1995) "An alternative eukaryotic DNA excision repair pathway." Mol. Cell. Biol. 15, 4572-4577.

Translational Cancer Genomics:

Recent advances in the use of genomic technology to understand cancer biology offer great hope for future treatment of human disease. It is becoming clear that microarray-based expression profiling of tumours can predict tumour characteristics such as lineage, prognosis, and likelihood of response to treatment. We are currently working on two projects aimed at using genomic technology to improve cancer diagnosis and treatment.

Details of these projects, and opportunities for trainees are coming soon...

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