Fidelity of basic biological processes is paramount to maintaining genomic integrity. A process required for all cells is the cell division cycle which consists of several checkpoints, ensuring genomic integrity and proper DNA replication before entry into mitosis. The most downstream effector prior to commitment to mitosis is checkpoint kinase 1 (Chk1). Although modifications that regulate Chk1 activity are well characterized the mechanisms of this regulation, including initiation, activation and inactivation are poorly understood. I have identified a predicted kinase associated 1 (KA1) domain and beta sheet C-terminal to the KA1 domain that are highly conserved from yeast to humans. I show that these regions are essential for Chk1 function and modification negatively regulates the G2/M checkpoint. In addition, understanding Chk1 regulation via these conserved regions provides the basis for the development of novel anticancer therapy.
|Advisor:||O'Connell, Matthew J.|
|Commitee:||Fisher, Robert, Manfredi, James J., Pfleger, Cathie|
|School:||Mount Sinai School of Medicine|
|School Location:||United States -- New York|
|Source:||MAI 49/05M, Masters Abstracts International|
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