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

作者：Spoerri Loredana; Brooks Kelly; Chia KeeMing; Grossman Gavriel; Ellis Jonathan J; Dahmer Heath Mareike; Skalamera Dubravka; Pavey Sandra; Burmeister Bryan; Gabrielli Brian^*

来源：Pigment Cell & Melanoma Research, 2016, 29(3): 329-339.

DOI：10.1111/pcmr.12466

• melanoma
• ATM
• checkpointarrest
• PLK1
• genomic instability

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.

• 出版日期2016-5
• 单位河北医科大学