Many commonly used chemotherapeutic drugs damage DNA and activate checkpoints that delay cell cycle progression. Many types of cancer show defects in checkpoint pathways and these defects are thought to contribute to genetic instability. The overall aim of this proposal is to use genetically modified human cells to determine how the kinases Chk1 and Chk2 trigger checkpoints in response to various forms of DNA damage and whether they function to maintain genetic stability.
Aim 1 is to determine the role of Chk2 in the therapeutic sensitivity of cancer cells. As mutations of the CHK2 gene are thought to contribute to several types of cancer, whether loss of Chk2-mediated checkpoints can sensitize cells to anticancer therapy will be examined. Checkpoint defects are thought to contribute to genomic instability, but how Chk2 contributes to tumorigenesis remains unclear.
Aim 2 will examine the role of Chk2 in maintaining genetic stability.
Aim 3 is to create a novel, isogenic human cancer cell system with which to examine the role of activation of the essential Chk1 kinase in cell cycle checkpoints and genomic stability.
| Wilsker, Deborah; Chung, Jon H; Bunz, Fred (2012) Chk1 suppresses bypass of mitosis and tetraploidization in p53-deficient cancer cells. Cell Cycle 11:1564-72 |
| Wilsker, Deborah; Bunz, Fred (2009) Chk1 phosphorylation during mitosis: a new role for a master regulator. Cell Cycle 8:1161-3 |
| Wilsker, Deborah; Petermann, Eva; Helleday, Thomas et al. (2008) Essential function of Chk1 can be uncoupled from DNA damage checkpoint and replication control. Proc Natl Acad Sci U S A 105:20752-7 |
| Wilsker, Deborah; Bunz, Fred (2007) Loss of ataxia telangiectasia mutated- and Rad3-related function potentiates the effects of chemotherapeutic drugs on cancer cell survival. Mol Cancer Ther 6:1406-13 |
