Karlene Cimprich

Honors and Awards

• Kimmel Scholar Award, Kimmel Foundation (1998)
• Burroughs Wellcome New Investigator Award in Toxicology, Burroughs Wellcome Foundation (1999)
• Beckman Scholar Award, Arnold and Mabel Beckman Foundation (2000)
• Leukemia and Lymphoma Scholar Award, Leukemia and Lymphoma Society (2004)

Professional Education

• B.S., University of Notre Dame Chemistry (1989)
• Ph.D., Harvard University Chemistry (1994)

Postdoctoral Advisees

• Robert Driscoll, Anja Duursma, Andrew Kile, Julie Sollier

Graduate & Fellowship Program Affiliations

• Cancer Biology
• Chemical and Systems Biology

Web Site Links

• Mole Pharm Lab Site

Current Research Interests

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, transcription, and the arrest of cell cycle progression. 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:

1) 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.

2) 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.

3) 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.

Publications

• A genome-wide siRNA screen reveals diverse cellular processes and pathways that mediate genome stability. Paulsen RD,  Soni DV, Wollman R, Hahn AT, Yee MC, Guan A, Hesley JA, Miller SC, Cromwell EF, Solow-Cordero DE, Meyer T, Cimprich KA.  Mol Cell.  2009; 35 (2): 228-39
• The structural determinants of checkpoint activation. MacDougall CA,  Byun TS, Van C, Yee MC, Cimprich KA.  Genes Dev.  2007; 21 (8): 898-903
• Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Byun TS,  Pacek M, Yee MC, Walter JC, Cimprich KA.  Genes Dev.  2005; 19 (9): 1040-52
• A novel protein activity mediates DNA binding of an ATR-ATRIP complex. Bomgarden RD,  Yean D, Yee MC, Cimprich KA.  J Biol Chem.  2004; 279 (14): 13346-53
• ATR kinase activity regulates the intranuclear translocation of ATR and RPA following ionizing radiation. Barr SM,  Leung CG, Chang EE, Cimprich KA.  Curr Biol.  2003; 13 (12): 1047-51
• A requirement for replication in activation of the ATR-dependent DNA damage checkpoint. Lupardus PJ,  Byun T, Yee MC, Hekmat-Nejad M, Cimprich KA.  Genes Dev.  2002; 16 (18): 2327-32
• Xenopus ATR is a replication-dependent chromatin-binding protein required for the DNA replication checkpoint. Hekmat-Nejad M,  You Z, Yee MC, Newport JW, Cimprich KA.  Curr Biol.  2000 Dec 14-28; 10 (24): 1565-73
• DNA damage tolerance: when it's OK to make mistakes. Chang DJ,  Cimprich KA.  Nat Chem Biol.  2009; 5 (2): 82-90
• HARPing on about the DNA damage response during replication. Driscoll R,  Cimprich KA.  Genes Dev.  2009; 23 (20): 2359-65
• ATR: an essential regulator of genome integrity. Cimprich KA,  Cortez D.  Nat Rev Mol Cell Biol.  2008; 9 (8): 616-27
• Probing ATR activation with model DNA templates. Cimprich KA,  Cell Cycle.  2007; 6 (19): 2348-54
• The ATR pathway: fine-tuning the fork. Paulsen RD,  Cimprich KA.  DNA Repair (Amst).  2007; 6 (7): 953-66
• Analyzing the ATR-mediated checkpoint using Xenopus egg extracts. Lupardus PJ,  Van C, Cimprich KA.  Methods.  2007; 41 (2): 222-31
• Phosphorylation of Xenopus Rad1 and Hus1 defines a readout for ATR activation that is independent of Claspin and the Rad9 carboxy terminus. Lupardus PJ,  Cimprich KA.  Mol Biol Cell.  2006; 17 (4): 1559-69
• Monoubiquitination of proliferating cell nuclear antigen induced by stalled replication requires uncoupling of DNA polymerase and mini-chromosome maintenance helicase activities. Chang DJ,  Lupardus PJ, Cimprich KA.  J Biol Chem.  2006; 281 (43): 32081-8
• Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase eta on ATR checkpoint signaling. Bomgarden RD,  Lupardus PJ, Soni DV, Yee MC, Ford JM, Cimprich KA.  EMBO J.  2006; 25 (11): 2605-14
• G2 damage checkpoints: what is the turn-on? O'Connell MJ,  Cimprich KA.  J Cell Sci.  2005; 118 (Pt 1): 1-6
• A cell-permeable, activity-based probe for protein and lipid kinases. Yee MC,  Fas SC, Stohlmeyer MM, Wandless TJ, Cimprich KA.  J Biol Chem.  2005; 280 (32): 29053-9
• Checkpoint adaptation; molecular mechanisms uncovered. Lupardus PJ,  Cimprich KA.  Cell.  2004; 117 (5): 555-6
• An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Costanzo V,  Shechter D, Lupardus PJ, Cimprich KA, Gottesman M, Gautier J.  Mol Cell.  2003; 11 (1): 203-13
• Fragile sites: breaking up over a slowdown. Cimprich KA,  Curr Biol.  2003; 13 (6): R231-3
• Enforced proximity in the function of a famous scaffold. Ferrell JE,  Cimprich KA.  Mol Cell.  2003; 11 (2): 289-91
• Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. Cliby WA,  Roberts CJ, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL, Friend SH.  EMBO J.  1998; 17 (1): 159-69
• Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Canman CE,  Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD.  Science.  1998; 281 (5383): 1677-9
• cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein. Cimprich KA,  Shin TB, Keith CT, Schreiber SL.  Proc Natl Acad Sci U S A.  1996; 93 (7): 2850-5