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Identification of Decatenation G₂ Checkpoint Impairment Independently of DNA Damage G₂ Checkpoint in Human Lung Cancer Cell Lines

¹ Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, and ² Division of Respiratory Medicine, Department of Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

It has been suggested that attenuation of the decatenation G₂ checkpoint function, which ensures sufficient chromatid decatenation by topoisomerase II before entering into mitosis, may contribute to the acquisition of genetic instability in cancer cells. To date, however, very little information is available on this type of checkpoint defect in human cancers. In this study, we report for the first time that a proportion of human lung cancer cell lines did not properly arrest before entering mitosis in the presence of a catalytic, circular cramp-forming topoisomerase II inhibitor ICRF-193, whereas the decatenation G₂ checkpoint impairment was present independently of the impaired DNA damage G₂ checkpoint. In addition, the presence of decatenation G₂ checkpoint dysfunction was found to be associated with diminished activation of ataxia-telangiectasia mutated in response to ICRF-193, suggesting the potential involvement of an upstream pathway sensing incompletely catenated chromatids. Interestingly, hypersensitivity to ICRF-193 was observed in cell lines with decatenation G₂ checkpoint impairment and negligible activation of ataxia-telangiectasia mutated. These findings suggest the possible involvement of decatenation G₂ checkpoint impairment in the development of human lung cancers, as well as the potential clinical implication of selective killing of lung cancer cells with such defects by this type of topoisomerase II inhibitor.

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