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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.,
DahmerHeath Mareike,
Škalamera Dubravka,
Pavey Sandra,
Burmeister Bryan,
Gabrielli Brian
Publication year - 2016
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12466
Subject(s) - genome instability , cell cycle checkpoint , chek1 , g2 m dna damage checkpoint , dna damage , cancer research , melanoma , biology , cell cycle , microbiology and biotechnology , mutation , spindle checkpoint , checkpoint kinase 2 , cell , genetics , cell division , dna , gene , spindle apparatus
Summary 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 CHK 2 is intact, but the cells are unable to maintain the cell cycle arrest due to elevated PLK 1 driving recovery from the arrest. Reducing PLK 1 activity recovered the ATM ‐dependent checkpoint arrest, and over‐expressing PLK 1 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 PLK 1, and a significant proportion of melanomas have high levels of PLK 1 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.