My laboratory investigates the regulation of cell cycle progression and genomic stability. Maintenance of genomic integrity is required for cellular viability and proliferation. As cells proliferate, chromosomes must be precisely duplicated and accurately segregated to prevent loss or inappropriate amplification of genetic information. Chromosomal instability and copy number alterations are frequently observed in cancer cells and are thought to contribute to tumorigenesis. Thus, even under optimal conditions, cell cycle progression is highly regulated. Moreover, eukaryotes have developed checkpoint pathways that monitor progress during cell division so that in the event of an error, the checkpoint is activated to block the cell cycle and activate repair pathways. Both cell cycle progression and checkpoint pathways are highly conserved from single-cell eukaryotes to multi-cellular organisms. A major focus of our work is aimed at understanding how ubiquitin-mediated degradation contributes to genomic stability via cell cycle and checkpoint pathways. Of particular interest is the F-box protein Dia2, which functions as part of an SCF ubiquitin ligase to regulate DNA replication and recovery from the replication checkpoint.
Selected Publications (Pubmed Search)
Fong C.M., Arumugam A., Koepp D.M. The Saccharomyces cerevisiae F-Box Protein Dia2 Is a Mediator of S-Phase Checkpoint Recovery from DNA Damage. Genetics. 2013 Feb;193(2):483-99. doi: 10.1534/genetics.112.146373. Epub 2012 Nov 19. PMCID: PMC3567738
Kim D.H., Zhang W., Koepp D.M. The Hect domain E3 ligase Tom1 and the F-box protein Dia2 control Cdc6 degradation in G1 phase. J Biol Chem. 2012 Dec 28;287(53):44212-20. doi: 10.1074/jbc.M112.401778. Epub 2012 Nov 5. PMCID: PMC3531739
Kim D.H., Koepp D.M. Hect E3 ubiquitin ligase Tom1 controls Dia2 degradation during the cell cycle. Mol Biol Cell. 2012 Nov;23(21):4203-11. doi: 10.1091/mbc.E12-07-0548. Epub 2012 Aug 29. PMCID: PMC3484099
Koepp DM. The replication stress response and the ubiquitin system: a new link in maintaining genomic integrity. Cell Div. 2010 Mar 10;5:8. PMID: 20219119; PMCID: PMC2841145
Kile A.C. and Koepp D.M. Activation of the S-phase checkpoint inhibits degradation of the F-box protein Dia2. Mol Cell Biol. 2010 Jan;30(1):160-71. Epub . PMID: 19858292; PMCID: PMC2798289
Swaminathan, S., Kile, A.C., MacDonald, E.M., Koepp, D.M. Yra1 is required for S phase entry and affects Dia2 binding to replication origins, Mol. Cell. Biol., 2007 Jul; 27(13):4674-84. Epub 2007 Apr 23. PMID: 17452447; PMCID: PMC1951488
Zhang, W. and Koepp, D.M. Fbw7 isoform interaction contributes to cyclin E proteolysis. Mol. Cancer Res., 2006 Dec; 4(12):935-43. PubMed PMID: 17189384.
Koepp, D.M., Kile, A.C., Swaminathan, S., Rodriguez-Rivera, V. The F-box protein Dia2 regulates DNA Replication, Mol. Biol. Cell, 2006 Apr, 17(4):1540-8, Epub Jan 18. PMID: 16421250; PMCID: PMC1415285