title: A novel ATM-dependent checkpoint defect distinct from loss of function mutation promotes genomic instability in melanoma.
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 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.
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.
authors: Loredana
authors: L
authors: Spoerri
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.
authors: Kelly
authors: K
authors: Brooks
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.|The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors: KeeMing
authors: K
authors: Chia
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.
authors: Gavriel
authors: G
authors: Grossman
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.
authors: Jonathan J
authors: JJ
authors: Ellis
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.
authors: Mareike
authors: M
authors: Dahmer-Heath
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.
authors: Dubravka
authors: D
authors: Škalamera
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.
authors: Sandra
authors: S
authors: Pavey
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.|Division of Cancer Services, Princess Alexandra Hospital, Brisbane, Qld, Australia.
authors: Bryan
authors: B
authors: Burmeister
authors: The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia.
authors: Brian
authors: B
authors: Gabrielli
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D042822:Genomic Instability / Q000235:genetics* / Q000528:radiation effects; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D008938:Mitosis / Q000528:radiation effects; D009154:Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011839:Radiation, Ionizing; D015854:Up-Regulation / Q000528:radiation effects; D000097869:Polo-Like Kinase 1
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
keywords: ATM; PLK1; checkpointarrest; genomic instability; melanoma