Identification of decatenation G2 checkpoint impairment independently of DNA damage G2 checkpoint in human lung cancer cell lines

It has been suggested that attenuation of the decatenation G(2) checkpoint function, which ensures sufficient chromatid decatenation by topoisomerase 11 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 11 inhibitor ICRF-193, whereas the decatenation G(2) checkpoint impairment was present independently of the impaired DNA damage G(2) checkpoint. In addition, the presence of decatenation G(2) 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. Interest ingly, hypersensitivity to ICRF-193 was observed in cell lines with decalenation G(2) checkpoint impairment and negligible activation of ataxiatelangiectasia mutated. These findings suggest the possible involvement of decatenation G(2) 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 11 inhibitor.