BIO: BSc (Biochemistry), PhD (Biochemistry); University of Western Ontario
Checkpoints are regulatory mechanisms that control the timing of transitions between cell cycle phases. Each checkpoint is regulated by a signal transduction cascade that can trigger cell cycle arrest in the presence of cellular damage. The best characterized checkpoints detect incorrect DNA structures, including physically damaged DNA, incompletely replicated DNA, or improperly formed mitotic spindles. Many of the components of these signal transduction cascades have been conserved throughout eukaryotic evolution, as similar genes have been found to regulate these processes in yeast and man. A number of genes that regulate checkpoints act as tumour suppressors in humans, including p53 and BRCA1.
Ongoing work involves characterization of yeast and human G2 checkpoint control genes, including hRAD1 and hRAD9 which were cloned in our lab. We have recently demonstrated protein-protein interactions between these and other G2 checkpoint control proteins, as well as other cell cycle regulators. We have also demonstrated the hRAD9 undergoes phosphorylation and complex rearrangements following irradiation, and we are currently studying the role of these changes in checkpoint signal transduction. Genetically, we are attempting to eliminate function of the human G2 checkpoint genes in mammalian cells and determine the effect this has on cellular responses to DNA damage.
We are also interested in the nature of DNA repair, particularly the Uve1-mediated repair in the fission yeast Schizosaccharomyces pombe. As with loss of checkpoint control, defects in DNA repair pathways have been linked with human cancers. These include mismatch repair defects which lead to hereditary colon cancer and xeroderma pigmentosum.
Current work in this area involves the characterization of Uve1 regulation through the checkpoint proteins Rad9 and Rad12. We have recently shown that Uve1 can initiate repair at base mismatches as well as at UV photoproducts, and that uve1 mutants exhibit elevated spontaneous mutation rates. We are currently studying the in vivo role of this enzyme by a both genetic and biochemical means.
Publications (individuals under my direct supervision are underlined):
- Feilotter, H.E., Michel, C., P. Uy, L. Bathurst, and S. DAVEY (2014). “BRCA1 haploinsufficiency leads to altered expression of genes involved in cellular proliferation and development.” PLoS One 9, e100068
- Kelly, R. and S. DAVEY (2013). “Tousled-like kinase-dependent phosphorylation of Rad9 plays a role in cell cycle progression and G2/M checkpoint exit.” PLoS One 8, e85859.
- Haslehurst, A.M., M. Koti, M. Dharsee, P. Nuin, K. Evans, J. Geraci, T. Childs, J. Chen, J. Li, J. Weberpals, S. DAVEY, J. Squire, P.C. Park, and H. Feilotter (2012). “EMT transcription factors snail and slug directly contribute to cisplatin resistance in serous epithelial ovarian cancer.” BMC Cancer 12, 91.
- Greer-Card, D.A., M. Sierant, and S. DAVEY (2010). " Rad9A is required for the G2 decatenation checkpoint and to prevent endoreduplication in response to topoisomerase II inhibition." J. Biol. Chem. 285, 15653-61.
- Sierant, M.L., N. Archer, and S. DAVEY (2010). “The Rad9A checkpoint protein is required for nuclear localization of the claspin adaptor protein.” Cell Cycle 9, 548-56.
- Singh, V., S. Nurmohamed, S. DAVEY, and Z. Jia (2007). "Tri-cistronic cloning, overexpression and purification of human Rad9, Rad1, Hus1 protein complex." Protein Expr. Purif. 54, 204-11.
- Pandita, R., G.S. Sharma, A. Laszlo, K.M. Hopkins, S. DAVEY, M. Chakhparonian, R.J. Wellinger, S.N. Powell, J.L. RotiRoti, H.B. Lieberman, and T. Pandita (2006). “Mammalian Rad9 plays a role in telomere stability, S- and G2-specific cell survival and homologous recombinational repair.” Mol. Cell. Biol. 26,1850-64.
- Bedard, L., M. Alessi, S. DAVEY, and T. Massey (2005). “Susceptibility to aflatoxin B1-induced carcinogenesis correlates with tissue-specific differences in DNA repair activity in mouse and rat.” Cancer Res. 65, 1265-70.
- 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.
- 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, 4829-35.
- 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, 26620-8.
- St.Onge, R.P., B.D.A. Besley, M. Park, R. Casselman, and S. DAVEY (2001). “DNA damage-dependent and -independent phosphorylation of the hRad9 checkpoint protein.” J. Biol. Chem. 276, 41898-905.
- 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, 4703-10.
- St. Onge, R.P., C.M. Udell, R. Casselman, and S. DAVEY (1999). "The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that forms complexes with hRAD1 and hHUS1." Mol. Biol. Cell. 10, 1985-95.
- Hang, H., S. J. Rauth, K.M. Hopkins, S. DAVEY, and H.B. Lieberman (1998). "Molecular cloning and tissue-specific expression of Mrad9, a murine orthologue of the Schizosaccharomyces pombe rad9+ checkpoint control gene." J. Cell. Physiol. 177, 232-40.
- Udell, C.M., S.K. Lee, and S. DAVEY (1998). “HRAD1 and MRAD1 encode mammalian homologues of the fission yeast rad1+ cell cycle checkpoint control gene.” Nucleic Acids Res. 26, 3971-8.
- DAVEY, S., C. Han, S.A. Ramer, J.C. Klassen, A. Jacobson, A. Eisenberger, K.M. Hopkins, H.B. Lieberman, and G.A. Freyer (1998). “Fission yeast rad12+ regulates cell cycle checkpoint control, and is homologous to the Bloom’s syndrome disease gene.” Mol. Cell. Biol. 18, 2721-8.
- DAVEY, S., M.L. Nass, J.V. Ferrer, K. Sidik, A. Eisenberger, D.L. Mitchell, and G.A. Freyer (1997). “The fission yeast UVDR DNA repair pathway is inducible.” Nucleic Acids Res. 25, 1002-8.
- 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, 13890-5.
- DAVEY, S., and D. Beach (1995). “RACH2, a novel human gene which complements a fission yeast cell cycle checkpoint mutation.” Mol. Biol. Cell 6, 1411-21.
- 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, 4572-7.
- Walworth, N., S. DAVEY, and D. Beach (1993). "Fission yeast chk1 protein kinase links the radcheckpoint pathway to cdc2." Nature 363, 368-71.
- DAVEY, S., and E.A. Faust. (1990) "Murine DNA polymerase α-primase initiates RNA-primed DNA synthesis preferentially upstream of a 3'-CC(C/A)-5' motif." J. Biol. Chem. 265, 3611-4.
- DAVEY, S., and E.A. Faust. (1990) "Murine DNA polymerase α fills gaps to completion in a direct assay. Altered kinetics of de novo DNA synthesis at single nucleotide gaps." J. Biol. Chem. 265, 4098-4104.
- Faust, E.A., R. Nagy, and S. DAVEY (1985). "Mouse DNA polymerase α-primase terminates and reinitiates DNA synthesis 2-14 nucleotides upstream of C2A1-2(C2-3/T2) sequences on a minute virus of mice DNA template." Proc. Natl. Acad. Sci. USA 82: 4023-7.