ࡱ> 8:79 R]bjbjT<]lJJJJJJJ^^^^^r ^4L===$& FTJ="====JJE====JJ===v=JJ~ .(^^=04==^^JJJJKarlene A. Cimprich, Ph.D. (Assistant Professor) Departmental Affiliation(s): Chemical and Systems Biology Graduate Program(s):  HYPERLINK "http://cancerio.stanford.edu/" Cancer Biology,  HYPERLINK "http://casb.stanford.edu/" Chemical and Systems Biology  Other Affiliation(s): Chemistry Phone: (650) 498-4720 Location: James H. Clark Center, Room W350B Email:  HYPERLINK "mailto:cimprich@stanford.edu" cimprich@stanford.edu Website:  HYPERLINK "http://cimprich.stanford.edu" \t "_blank" http://cimprich.stanford.edu  Keywords: cell cycle regulation, cell cycle checkpoint, DNA damage, DNA repair, genomic stability, chemical biology, ATR kinase, signal transduction Research Description: My lab is focused on understanding the mechanism that the cell uses to maintain genomic stability, with an emphasis on DNA damage checkpoints. Components of these checkpoints effectively monitor the status of the genome, sensing the presence of DNA damage and coordinating a range of possible responses, including DNA repair, apoptosis, arrest of cell cycle progression, and maintenance of replication fork stability. Loss of this checkpoint response is a hallmark of cancer cells and is one of the early steps in the development of cancer. We are studying the DNA damage response using both cell-free extracts derived from the eggs of the frog Xenopus laevis as well as cultured mammalian cells. We are using these systems and a range of multidisciplinary techniques to understand how the checkpoint is activated following DNA damage and how this pathway is integrated with the processes of DNA replication, cell cycle progression and DNA repair. Specific areas of current interest are: Checkpoint Activation. The actual nature of the signal(s) sensed by the cell and the mechanism by which damage detection occurs is not known. We have found that replication plays a critical role in this process, and we are now working to define the nature of the signal formed during DNA replication and the precise role of replication in generating this signal. Checkpoint Signaling . Using biochemical and microscopy-based approaches, we study the proteins that recognize the checkpoint activating signal, including ATR, ATRIP and the 9-1-1 complex. We are interested in how these proteins are regulated and the role that protein localization plays in this process. We are also working to identify downstream targets of the checkpoint relevant to repair, cell cycle arrest and checkpoint recovery. Chemical Modulation of Checkpoint Pathways . We are using small, organic molecules to analyze checkpoint activation, profile the activity of the checkpoint kinases and identify new targets of the checkpoint. We are also developing new assays to screen for molecules that activate or inhibit the DNA damage checkpoint. Representative Publication(s): Cimprich KA, Shin TB, Keith CT and Schreiber SL. (1996) cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein. Proc. Natl. Acad. Sci. USA 99, 2850-2855. Cliby WA, Roberts CA, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL and Friend SH. (1998) Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA damaging agents and defects in cell cycle checkpoints. EMBO J. 17, 159-169. Lupardus, P. J., Byun, T., Yee, M-C., Hekmat-Nejad, M. and Cimprich, K. A. (2002) A Requirement for replication in activation of the ATR-dependent DNA damage checkpoint. Genes and Development, 16, 2327-2332. Hekmat-Nejad, M., You, Z., Yee, M-C., Newport, J. W., Cimprich, K. A. (2000) Xenopus ATR is a replication-dependent chromatin binding protein required for the DNA replication checkpoint. Current Biology, 10, 1565-1573. Cimprich, K. A. (2003) Fragile sites: breaking up over a slowdown. Current Biology , 13, R231-R233. Barr, S. M., Leung, C. G., Chang, E. E., Cimprich, K. A. (2003) ATR kinase activity regulates the intranuclear translocation of ATR and RPA following ionizing radiation. Current Biology, 13, 1047-1051. Bomgarden, R., Yean, D., Yee, M-C., Cimprich, K. A. (2004) A novel protein activity mediates DNA binding of an ATR-ATRIP complex. J. Biol. Chem . 14, 13346-13353. 23Om )/?IkqrsH W w  ƲƲƲƲƲƲƲƲƃ!0JB*CJOJQJ^JaJph333 >*B*CJOJQJ^JaJph0JCJOJQJ^JaJ&jB*CJOJQJU^JaJph333B*CJOJQJ^JaJph333!0JB*CJOJQJ^JaJph3331jB*CJOJQJU^JaJmHnHph333u33)w  4\]] ) 3;I\]!0JB*CJOJQJ^JaJph333B*CJOJQJ^JaJph333!0JB*CJOJQJ^JaJph333 0182P. 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