DNA Damage and Genomic Instability Induced by Inappropriate DNA Re- replication; Annual summary rept. 24 Mar 2005-23 Mar 2006

摘要

Chromosomal rearrangements and changes in copy number at various genomic loci are hallmarks of cancer cells and may be very early steps in tumorigenesis. The origins of genomic insults are poorly understood and this proposal aims to characterize one potential source of genomic instability, inappropriate DNA re-replication. In a normal eukaryotic cell cycle, the chromosomal DNA of a cell is replicated once, and only once, during S phase to ensure that each daughter cell receives exactly one complement of genomic material. By perturbing the regulation of several proteins involved in replication initiation, our laboratory has been able to conditionally induce varying amounts of re-replication in yeast cells. In the prior reporting period we demonstrated that re-replication induces a rapid and significant decrease in cell viability and a cellular DNA damage response. Strikingly, we have observed DNA damage in the absence of a classical replication stress response. In this reporting period we have demonstrated that re-replication leads to genome instability, in particular gene duplication. This is the first experimental evidence that re-replication might contribute to gene amplification and thus tumorigenesis.