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  • A novel ATM-dependent checkpoint defect distinct from loss of function mutation promotes genomic instability in melanoma

    Author(s)
    Spoerri, Loredana
    Brooks, Kelly
    Chia, KeeMing
    Grossman, Gavriel
    Ellis, Jonathan J
    Dahmer-Heath, Mareike
    Skalamera, Dubravka
    Pavey, Sandra
    Burmeister, Bryan
    Gabrielli, Brian
    Griffith University Author(s)
    Gabrielli, Brian
    Year published
    2016
    Metadata
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    Abstract
    Melanomas have high levels of genomic instability that can contribute to poor disease prognosis. Here, we report a novel defect of the ATM-dependent cell cycle checkpoint in melanoma cell lines that promotes genomic instability. In defective cells, ATM signalling to CHK2 is intact, but the cells are unable to maintain the cell cycle arrest due to elevated PLK1 driving recovery from the arrest. Reducing PLK1 activity recovered the ATM-dependent checkpoint arrest, and over-expressing PLK1 was sufficient to overcome the checkpoint arrest and increase genomic instability. Loss of the ATM-dependent checkpoint did not affect ...
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    Melanomas have high levels of genomic instability that can contribute to poor disease prognosis. Here, we report a novel defect of the ATM-dependent cell cycle checkpoint in melanoma cell lines that promotes genomic instability. In defective cells, ATM signalling to CHK2 is intact, but the cells are unable to maintain the cell cycle arrest due to elevated PLK1 driving recovery from the arrest. Reducing PLK1 activity recovered the ATM-dependent checkpoint arrest, and over-expressing PLK1 was sufficient to overcome the checkpoint arrest and increase genomic instability. Loss of the ATM-dependent checkpoint did not affect sensitivity to ionizing radiation demonstrating that this defect is distinct from ATM loss of function mutations. The checkpoint defective melanoma cell lines over-express PLK1, and a significant proportion of melanomas have high levels of PLK1 over-expression suggesting this defect is a common feature of melanomas. The inability of ATM to impose a cell cycle arrest in response to DNA damage increases genomic instability. This work also suggests that the ATM-dependent checkpoint arrest is likely to be defective in a higher proportion of cancers than previously expected.
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    Journal Title
    Pigment Cell & Melanoma Research
    Volume
    29
    Issue
    3
    DOI
    https://doi.org/10.1111/pcmr.12466
    Subject
    Biological sciences
    Biomedical and clinical sciences
    Science & Technology
    Life Sciences & Biomedicine
    Oncology
    Cell Biology
    Dermatology
    Publication URI
    http://hdl.handle.net/10072/409331
    Collection
    • Journal articles

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