Cancer cells are created through accumulated DNA mutations in somatic cells, where cellular DNA is constantly assaulted by exogenous agents and cellular metabolites. Normal cells have mechanisms for monitoring genomic DNA integrity and repairing the DNA mutations, while cancer cells frequently lose the ability to efficiently respond to DNA damage, facilitating the accumulation of mutations that lead to deregulated growth. A critical cellular response to DNA damage is the arrest of the cell cycle, thereby providing time for repair before DNA replication or mitosis. The mechanisms of DNA damage-induced cell cycle arrest are complex, and many components of the signal transduction pathway are unknown. The zebrafish has considerable advantages as a vertebrate model for the discovery of DNA damage response genes. By screening zebrafish embryos in the Hopkins' insertional mutant collection, two recessive embryonic lethal mutations were identified that abrogate DNA damage-induced cell cycle arrest. The genes affected by these mutations have been cloned, and they have human homologues with high similarity, but little is known about their functions. The function of these genes in the DNA damage checkpoints of human cells will be examined. Also, the Hopkins' mutant collection will be screened for additional DNA damage checkpoint failure mutants.

F32GM074366

2005-04-01

2008-03-31