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Cell cycle checkpoint control in response to DNA damageCell cycle checkpoints ensure the integrity of the genome from one replicative cell cycle to the next. In the event of catastrophic damage to the genome. cells of multicellular eukaryotes can undergo apoptosis. presumably to eliminate them from the cell population and reduce the risk of propagating genetically unstable cells. Alternatively. cells may respond to DNA damage by undergoing a transient arrest of the cell cycle. which correlates with their ability to survive exposure to DNA damaging agents. This response requires the DNA damage checkpoint pathway; if compromised by mutation or drug treatment. cells will enter mitosis with damaged DNA and die. The fission yeast has been an extremely valuable system for identifying and characterizing components of the DNA damage checkpoint. Indeed. many proteins that are now known to function in the checkpoint pathway in mammalian cells were identified solely based on their sequence homology to proteins that were identified genetically and functionally in yeast. Thus. it is clear that the identification of proteins in yeast using the power of classical genetics is a valid and productive means of identifying and gaining insight into the function of mammalian counterparts. My laboratory aims to understand the mechanism through which the protein kinase Chk1 controls the DNA damage checkpoint in eukaryotic cells. Using a combined genetic and biochemical approach. we focus much of our effort on dissecting the molecular events that control Chk1 function and the targets of Chk1 that regulate cell cycle progression. We have initiated studies on Msc1. a protein found to compensate for loss of Chk1 function that is homologous to a tumor suppressor binding protein in mammalian cells. The Msc1 protein appears to be important for histone modifications of chromatin. for genomic stability and for survival after DNA damage. Future directions will explore the cellular role of Msc1 in these processes. Selected PublicationsPalermo C, Hope JC, Freyer GA, Rao H, Walworth NC. (2008) Importance of a C-terminal conserved region of Chk1 for checkpoint function. PLoS ONE. 3(1):e1427. Ahmed S, Dul B, Qiu X, Walworth NC.(2007) Msc1 acts through histone H2A.Z to promote chromosome stability in Schizosaccharomyces pombe. Genetics. 177(3):1487-97. Dul BE, Walworth NC. (2007) The plant homeodomain fingers of fission yeast Msc1 exhibit E3 ubiquitin ligase activity. J Biol Chem. 282(25):18397-406. Dunaway. S.. Liu. H.-Y. and Walworth. N. C. (2005). Interaction of 14-3-3 protein with Chk1 affects localization and checkpoint function. J. Cell Science 118:39-50. Palermo. C. and Walworth. N. C. (2005). Assaying Cell Cycle Checkpoints: Activity of the Protein Kinase Chk1. in Methods in Molecular Biology. vol. 296. Cell Cycle Control: Mechanisms and Protocols. pages 345-354. T. Humphrey and G. Brooks. eds. Humana Press Inc. Ahmed. S.. Palermo. C.. Wan. S. and Walworth. N. C. (2004). A novel protein with similarities to Rb binding protein 2 compensates for lack of Chk1 function and affects histone modification in fission yeast. Molecular and Cellular Biology 24(9):3660-3669. Dunaway. S. and Walworth. N. C. (2004). Assaying the DNA damage checkpoint in fission yeast. Methods. 33:260-263. Colon-Berlingeri. M. and Walworth. N. C. (2003). Use of in vivo Gap Repair for Isolation of Mutant Alleles of a Checkpoint Gene. in Methods in Molecular Biology. vol. 241: Cell Cycle Checkpoint Controls Protocols. pages 175-187. H. B. Lieberman. Ed. Humana press Inc.. Totowa. NJ. Liu. H.Y.. Nefsky. B. S. and Walworth. N. C. (2002). The Ded1 DEAD box helicase interacts with Chk1 and Cdc2. J. Biological Chemistry 277:2637-2643. Capasso. H.. Palermo. C.. Wan. S.. Rao. H.. John. U. P.. O'Connell. M. J.. Walworth. N. C. (2002). Phosphorylation activates Chk1 and is required for checkpoint-mediated cell cycle arrest. J. Cell Science 115:4555-4564. Wan. S. and Walworth. N. C. (2001). A novel genetic screen yields checkpoint defective alleles of Schizosaccharomyces pombe chk1. Current Genetics 38:299-306. Walworth. N.C. (2001). DNA damage: Chk1 and Cdc25. more than meets the eye. Current Opinion in Genetics and Development 11:78-82. O'Connell. M.J.. Walworth. N. C. and Carr. A. M. (2000). The G2-phase DNA-damage checkpoint. Trends in Cell Biology. 10:296-303. Walworth. N.C. (2000). Cell-cycle checkpoint kinases: checking in on the cell cycle. Current Opinion in Cell Biology 12:697-704. |
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