Wide spread genomic instability is a hallmark of human tumors. The most obvious manifestation of genomic instability results in large-scale chromosomal rearrangements. These chromosomal rearrangements can lead to Loss of-Heterozygosity (LOH) or novel gene fusions encompassing chromosome regions known to contain oncogenes and/or tumor suppressor genes. The events that lead to chromosome rearrangement appear to be a result of aberrant recombination processes which are initiated by recombinational repair during normal cell growth and following environmentally and radiation induced damage. The long-term goal of this research is to understand the biochemical processes that lead to chromosomal rearrangement. In this renewal grant application we propose a two-pronged approach that combines: 1.) biochemical, molecular and structure/function analysis of expressed and purified proteins derived from cloned human genes involved in recombinational repair (Specific Aims I - IV) and 2.) a dormant genetic analysis of mutations in these human genes found in tumor cells, recombinant mutations predicted to be important from our structure/function analysis and anti-sense suppression of normal gene expression (Specific Aim V). Such combined approaches should provide an interactive dialogue where the biochemical, molecular and structure/function studies will help focus on important protein activities while the genetic analysis will identify cellular dysfunction produced by these altered proteins. The focus of these studies will be on the initiation events in the recombinational repair process since these are likely to be rate-limiting. We have amassed seven human genes that are implicated in the initiation of recombinational repair by virtue of their related enzymatic activities or their homology to yeast genes where both genetic and biochemical evidence underscores a role in recombinational repair. These studies will contribute to our understanding of the processes involved in maintaining human chromosome stability and should provide a framework for the design of more efficacious chemotherapeutic and radiotherapeutic methodologies as well as preventive therapeutic modalities designed to control chromosome stability
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