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  • ATM dependent initiation of radiation induced G M

    2023-01-28

    ATM-dependent initiation of radiation-induced G2/M checkpoint arrest is well established [11], [34], [35]. However, the ATR pathway may also be involved [36], [37]. Brown and Baltimore generated Cre/lox-conditional cell lines or 1 98 with a kinase inactive allele of ATR (ATRkd) to evaluate the role of ATR in checkpoint responses to γ rays, which demonstrated that after IR treatment, ATR and ATM each contribute to the early delay in M-phase entry but that ATR played the major role in the late phase. Double deletion of ATR and ATM eliminates nearly all IR-induced delay, indicating that these two kinases cooperate in IR-induced G2/M-phase checkpoint [36]. However, using specific inhibitors in A-T cells, we found that ATR plays a pivotal role to regulate the early G2/M arrest after exposure to doses as low as 0.2Gy heavy ion radiation, while above 2Gy for X-rays, which has also been proved in ATM proficient cells. The data indicate that the ATR pathway may be involved in the mechanism of HRS/IRR induced by heavy ion beams. Analysis of survival using a specific ATR inhibitor confirm this speculation. Marples et al. have also shown that abrogation of the G2/M checkpoint through inhibition of CHK1 and CHK2 after low LET radiation prevents the activation of the early G2 checkpoint and inhibits the development of the IRR response by extending the HRS response to higher doses [3]. Continued studies will be necessary to determine how ATM and ATR cooperate in the mechanism of early G2/M checkpoint and the corresponding HRS/IRR response after irradiation. To date, there was no direct evidence for activation of the ATR pathway by irradiation of different LETs. However, the analysis of DSB repair pathway choice is an attractive topic in the DNA damage response (DDR) field [38], [39], [40], [41], and such analysis indicates that the two pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR), function differentially in response to different kinds of irradiation. The efficiency of NHEJ is reported to be diminished for complex DSBs [42], [43], [44]. Using different particle radiation in human cells, Yajima proved that the complexity of DSBs was a critical factor enhancing DNA end-resection. Hence, particle irradiation can more efficiently trigger HR repair than sparsely ionizing radiation. As the end-resection of DSBs as 1 98 well as single strand DNAs (ssDNAs) can cause the ssDNA tails that are a signal for activation of the ATR signaling pathway, Yajima speculated that the ATR may function as the primary kinase for checkpoint arrest in G2 cells following heavy ion radiation [19]. We substantiated this proposal by showing that regulation of the G2/M checkpoint requires activation of the ATR pathway and is ATM-independent, in an LET-dependent manner, indicating that the ATR pathway can play a more important role under high LET radiation, including the mechanism of HRS/IRR effect. In this study, DNA-PKcs was also found to interfere with the mitotic index at early times post IR. However, by adding colcemid, we showed that DNA-PKcs enhances the mitotic index through interfering with mitotic exit. Several papers reported that DNA-PKcs is not only a major player in the nonhomologous end joining pathway for DNA DSB repair, but also functions during mitosis. Depletion of DNA-PKcs protein or inhibition of DNA-PKcs kinase activity can result in delay of mitotic transition due to chromosome misalignment [45], [46]. The involvement of DNA-PKcs in the HRS/IRR response has been studied by Vaganay-Juery et al. in 10 human cancer cell lines (6HRS+ and 4HRS− cell lines). Strikingly, a decrease in DNA-PK activity following a 0.2Gy irradiation was only found in the six cell lines exhibiting HRS, whereas the DNA-PK activity increased in four cell lines which did not exhibit HRS [2], [47]. Thus, additional studies are warranted to define the mechanism by which DNA-PKcs influences in HRS/IRR, and whether this occurs via its function in DSB repair or mitosis.