Fragile Chromosome Instability and Cell Cycle Checkpoint Genes

University Of Arizona, Tucson AZ

Investigators

Abstract

Checkpoints were first identified as regulatory controls that stop the cell cycle after DNA damage. Such arrests of the cell cycle allow time for efficient replication and repair. Checkpoint genes are those that cause these arrests after DNA damage; checkpoint mutants fail to do so and either exhibit genome instability and/or die. The mechanisms by which wild-type checkpoint genes ensure genome stability are still poorly understood, mainly for two reasons. First, individual checkpoint genes have roles in multiple checkpoints (e.g., one gene is essential for arrest during both DNA replication and chromosome segregation) and can have roles in other aspects of DNA metabolism as well (e.g., dNTP synthesis, stability of DNA replication forks, telomere synthesis). Second, genome instability is itself a complex process involving the gain or loss of whole chromosomes, and novel, sometimes complex chromosomal rearrangements. To understand how checkpoint genes stabilize a genome, the investigator has developed a model of chromosome instability termed "fragile site instability." This instability can involve DNA breaks and recombination in a defined chromosomal region (a fragile site), the formation of multiply rearranged chromosomes, and a high frequency of aberrations in checkpoint mutants. Recent data from the investigator's laboratory suggest that fragile site instability may be linked to defects in DNA replication. This project is designed to reveal how instability is linked to specific DNA sequences in the fragile site, to checkpoint gene dysfunctions, and to DNA replication. The multiple links between checkpoint gene function and genome stability are important to understand because perturbations of genome stability have profound effects on the functioning of all organisms. Thus this project may lead to insights that will benefit all of society. In addition, the investigator will continue his educational activities, which in the past have included mentoring individuals from the level of high school students to postdoctoral fellows.