Technical Details:
To assess the role of BLM in genetic instability, we generated cells that lack functional BLM genes. Genetic instability appears to be required for a normal colorectal epithelial cell to evolve into a cancerous one. Bloom syndrome patients have a strong predisposition to cancer that affects a variety of tissues. The mechanism of disease is attributed to genomic instability, but many questions about the nature of this instability have not yet been answered. To investigate these issues, we used gene targeting techniques to disrupt the BLM gene in karyotypically stable colorectal cancer epithelial cells. BLM knockout cells showed an increased tendency of sister chromatids to exchange DNA strands and were substantially more likely to undergo homologous recombination at chromosomal loci than parental cells. BLM-deficient cells did not display gross chromosomal rearrangements nor a change in the rates of chromosome gains and losses. However, the enhanced homologous recombination was associated with losses of heterozygosity distributed throughout the genome. These observations define a type of genetic instability that has significant implications for the evolution of cancer.
Looking for Partners:
Isogenic cell lines with or without intact BLM genes are valuable reagents for studying aneuploidy in human cancers.. They can also be used for identifying novel small molecules that are dependent on genetic instability to induce apoptosis in human cancer cells, which can potentially be used as chemotherapeutic or chemopreventive agents.
