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DNA Damage and Genomic Instability Induced by Inappropriate DNA Re-replication

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Annual summary rept. 24 Mar 2004-23 Mar 2007

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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. We have demonstrated that re-replication induces a rapid and significant decrease in cell viability and a cellular DNA damage response. We elected to focus our studies of genome instability on gene amplification because of its clinical importance in breast cancer. We have shown that re-replication is a potent inducer of gene amplification that generates structures similar to amplicons seen but poorly understood in tumors. The high frequency at which these amplification structures are generated is specific to re-replication as similar structures are not observed when S phase DNA replication is impaired or DNA is directly damaged. We thus propose that re- replication arising from loss of replication control is a potential source of the genomic instability important for tumorigenesis.

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  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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