Dynamics of mitotic structures in chromosomally unstable cell lines

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Project objective

Chromosomal instability is a common feature of cancer cells, but the mechanisms of instability are largely unknown. The aim of this project is to explore the relationship between instability and loss of a specific pathway of DNA damage repair, known as homologous recombination repair (HRR). We have observed that HRR-deficient cells have high levels of spontaneous chromosome missegregation and that the structure of centrosomes, a component of the mitotic spindle, is defective in these cells (Griffin et al. 2000 Nature Cell Biol., 2, 757-761). We have knocked out one of the HRR genes (Xrcc2) in mice and will use Xrcc2-deficient mouse embryonic fibroblasts (MEFs), as well as HRR-deficient MEF.s carrying a disruption of the breast cancer-predisposition gene Brca2, to explore the nature of this defect. Time-lapse microscopy will be used with fluorescently-tagged mitotic structures to explore the mechanism of centrosome disruption and determine the stage of abnormal centrosome development in these cells. Additionally we will see if physical links occur between HRR proteins and the centrosome, by attempting to co-localize XRCC2 with centrosomes. These studies should further our understanding of the processes guarding our genome from chromosomal losses and gains.

Original text from CORDIS.

Participants

• MEDICAL RESEARCH COUNCIL · LONDONCoordinatorUnited Kingdom

Links

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