Compared with low linear energy transfer (LET) radiation,
carbon-ion radiation has been proved to induce high frequency of more complex
DNA damages, including
DNA double strands (DSBs) and non-
DSB clustered DNA lesions. Chemotherapeutic
drug doxorubicin has been reported to elicit additional H2AX phosphorylation in
polyploidy. Here, we investigated whether mitotic DNA damage induced by high-LET
carbon-ion radiation could play the same role. We demonstrate that impairment of post-mitotic G1 and S arrest and abrogation of post-mitotic G2-M checkpoint failed to prevent mis-replication of damaged
DNA and mis-separation of chromosomes. Meanwhile, mitotic slippage only
nocodazole-related, cytokinesis failure and cell fusion collectively contributed to the formation of binucleated cells. Chk1 and Cdh1 activation was inhibited when
polyploidy emerged in force, both of which are critical components for mitotic exit and cytokinesis.
Carbon-ion radiation irrelevant of
nocodazole incurred additional DNA breaks in
polyploidy, manifesting as structural and numerical karyotype changes. The proliferation of cells given pre-synchronization and radiation was completely inhibited and cells were intensely apoptotic. Since increased chromosomal damage resulted in extensive H2AX phosphorylation during
polyploidy, we propose that the additional γ-H2AX during
polyploidy incurred by
carbon-ion radiation provides a final opportunity for these dangerous and chromosomally unstable cells to be eliminated.