Cell cycle regulation is defective in cancer cells, which proliferate at inappropriate times and locations in vivo. The mechanism regulating the switch between quiescence and proliferation is compromised, and cancer cells continue to cycle under conditions which halt the proliferation of normal cells. Further, the normal cell cycle is designed to ensure that the key events in the cycle occur in the appropriate order, so that cells do not proceed into mitosis without having first duplicated their genome, for example. Genomic instability often seen during cancer development and progression can result from deranging these controls.

We use the budding yeast Saccharomyces cerevisiae, as well as mammalian cells, as models in which to study the regulation of DNA replication and the DNA damage response. Genetic studies of the cell cycle in yeast have identified many proteins involved in regulating progression from G1 phase into S phase, proteins involved in the DNA damage response, and proteins important for genomic stability. The highly conserved nature of these processes makes study of the yeast cell cycle directly relevant to higher eukaryotes, including humans. The ease of genetic manipulation in yeast makes these model systems ideal for introducing changes into proteins and examining the effects of these changes on cellular processes. Functional genomic and proteomic approaches are well established in yeast and provide a means of studying these processes on a genome-wide scale.

DNA damage foci

Single molecule analysis of
replicating DNA

Vaisica J.A., Baryshnikova A., Costanzo M., Boone C., Brown G.W. (2011)
Mms1 and Mms22 Stabilize the Replisome During Replication Stress.
Mol Biol Cell 22: 2396-2408
Abstract | Full Text

Berbenetz N., Nislow C., Brown G.W. (2010)
Diversity of Eukaryotic DNA Replication Origins Revealed by Genome-wide Analysis of Chromatin Structure.
PLoS Genetics 6: e1001092.
Abstract | Full Text

Yang J., Bachrati C.Z., Ou J., Hickson I.D., Brown G.W. (2010)
Human Topoisomerase IIIα Is a Single-stranded DNA Decatenase That Is Stimulated by BLM and RMI1.
J Biol Chem 285: 21426-36.
Abstract | Full Text

Davidson M.B. and Brown G.W. (2009)
Dissecting the DNA damage response using functional genomics approaches in S. cerevisiae. DNA Repair 8: 1110-1117.
Abstract | Full Text

Yu L, Lopez A, Anaflous A, El Bali B, Hamal A, Ericson E., Heisler L.E., McQuibban A., Giaever G., Nislow C., Boone C., Brown G.W., Bellaoui M.(2008)
Chemical–Genetic Profiling of Imidazo[1,2-a]pyridines and -Pyrimidines Reveals Target Pathways Conserved between Yeast and Human Cells
PLoS Genetics 4: e1000284.
Abstract | Full Text

Davidson M.B. and Brown, G.W. (2008)
The N- and C-termini of Elg1 contribute to the maintenance of genome stability
DNA Repair 7: 1221-1232.
Abstract | Full Text

Roberts, T.M., Waris Zaidi, I., Vaisica, J.A., Peter, M., Brown, G.W. (2008)
Regulation of Rtt107 Recruitment to Stalled DNA Replication Forks by the Cullin Rtt101 and the Rtt109 Acetyltransferase. Molecular Biology of the Cell 19: 171-180.
Abstract | Full Text | Faculty of 1000 Evaluation

Xu, H., Boone, C., Brown, G. W. (2007)
Genetic Dissection of Parallel Sister Chromatid Cohesion Pathways. Genetics 176: 1417-1429.
Abstract | Full Text

Yu, L., Pena Castillo, L., Mnaimneh, S., Hughes, T. R., Brown, G. W. (2006) A Survey of Essential Gene Function in the Yeast Cell Division Cycle. Molecular Biology of the Cell 17: 4736-4747.
Abstract | Full Text

Chang, M., Parsons, A. B., Sheikh, B. H., Boone, C., and Brown, G. W. (2006) Genomic Approaches for Identifying DNA Damage Response Pathways in S. cerevisiae. Methods in Enzmology 409: 213-35.
Abstract | Full Text

Zhang, C., Roberts, T. M., Yang, J., Desai, R., Brown,
G. W. (2006) Suppression of Genomic Instability by SLX5 and SLX8 in Saccharomyces cerevisiae. DNA Repair 5: 336-46.
Abstract | Full Text

Roberts, T. M., Kobor, M. S., Bastin-Shanower, S. A., Ii, M., Horte, S. A., Gin, J.W., Emili, A., Rine, J., Brill, S. J., Brown, G. W. (2006) Slx4 Regulates DNA Damage Checkpoint-dependent Phosphorylation of the BRCT Domain Protein Rtt107/Esc4. Mol. Biol. Cell, 17: 539-548.
Abstract | Full Text

Chang, M., Bellaoui, M., Zhang, C., Desai, R., Morozov, P., Delgado-Cruzata, L., Rothstein, R., Freyer, G. A., Boone, C., and Brown, G.W. (2005)
RMI1/NCE4, a Suppressor of Genome Instability, Encodes a Member of the RecQ Helicase/Topo III Complex.EMBO J., 24: 2024-2033.
Abstract | Full Text

Bellaoui, M., Chang, M., Ou, J., Xu, H., Boone, C., and Brown, G. W. (2003) Elg1 forms an alternative RFC complex important for DNA replication and genome integrity. EMBO J. 22: 4304-4313. Abstract | Full Text | Commentary in Curr. Biol.

Chang, M., Bellaoui, M., Boone, C., and Brown, G. W. (2002) A genome-wide screen for methyl methanesulfonate-sensitive mutants reveals genes required for S phase progression in the presence of DNA damage. Proc. Natl. Acad. Sci. USA 99: 16934-16939. Abstract | Full Text

Brown, G. W. and Kelly, T. J. (2000) Regulation of DNA Replication. Ann. Rev. Biochem. 69: 829-880. Abstract | Full Text

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