Nancy C. Walworth
Robert Wood Johnson Medical School
Dept. of Pharmacology
Piscataway, NJ 08854
Cell cycle checkpoint control in response to DNA damage
Cell 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.