||DNA Repair Processes and Checkpoint Pathways in Human Cells Exposed to Heavy Ion Beams
Yajima, HirohikoXUE, Lian
International Journal of Particle Therapy
The DNA double-strand break (DSB) is the most deleterious of the ionizing radiation- induced DNA damages. Two major repair pathways for DSBs have been well studied, nonhomologous end-joining and homologous recombination. It is known that high linear energy transfer radiation, such as heavy ion beams, induces complex DSBs with clustered damages at the end and that, as a result, the efficiency of nonhomologous end- joining in repairing these DSBs is diminished. We have shown that more than 80% of complex DSBs in S/G2 human cells are subjected to DNA end resection, an early step in homologous recombination to generate single-strand DNA. Furthermore, recent work, including ours, revealed that a subpopulation of human G1 cells exhibit resection activity following ionizing radiation, which is dependent on CtIP, as in other cell cycle phases, and also dependent on the complexity of the DSB. Collectively, this recent progress indicates that the complexity of the DSB structure drastically enhances end resection, with CtIP being a significant factor required for complex DSB repair throughout the cell cycle. We further revealed that the ATR pathway, which is activated by end resection, plays a pivotal role in regulating early G2/M arrest in ATM-deficient cells exposed to high linear energy transfer ion beams. This suggests that the complexity of the DSB also influences the choice of the signaling pathway via the enhanced resection. Additionally, we discuss a possibility that CtIP has an additional function (or functions) after the initiation of resection. In conclusion, new findings and insight are pivotal to allow innovative progress in heavy ion-particle therapy by shedding light on the whole response at the molecular level in cells exposed to heavy ion beams.