The Roles of Chromosome Breaks and Telomere Dynamics in the Genomic Instability Associated With Human Breast Cancer.
Annual rept. 11 Aug 97-10 AUg 98
BAYLOR COLL OF MEDICINE HOUSTON TX
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Human tumors acquire a marked genomic instability as part of their progression from normal to malignant cells. This instability is likely due in part to the progressive shortening and transient loss of telomeres from chromosome ends. Loss of telomeres allows chromosomes to fuse end-to-end, triggering chromosome fusion- bridge-breakage cycles that lead to genome rearrangements, loss of heterozygosity, and gene amplification. The initial steps in chromosome fusion-bridge-breakage cycles are being studied by introducing site-specific double-strand breaks adjacent to interstitial telomere sequences in a marked region of specially engineered test chromosome, A modified gene for the Green Fluorescent Protein GFP is being constructed to permit detection of chromatid fusion, the first step in fusion-bridge-breakage cycles. By varying the length of the telomere sequence, we can measure the length of telomere sequence that is required to protect chromosome ends and prevent genomic instability in breast cancer cells. A test chromosome is being constructed using the APRT locus in CHO cells, which will permit a measure of the effects of telomere sequences on the frequencies of chromatid fusion and chromosome loss. After these initial studies we will transfer the engineered hamster chromosome by microcell fusion into human breast cancer cells at different tumor stages.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research