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  • ATM is required for the proper function of

    2023-12-06

    ATM is required for the proper function of the DNA-repair pathway in response to bleomycin-induced DNA damage in mammalian cells [55], [56]. Recent reports suggest that ATM activation by double-strand breaks leads to the subsequent ATR activation [57], [58], [59]. The recruitment of ATR to double-strand breaks requires RPA-coated single-stranded DNA, a structure generated by the nuclease-mediated resection of double-strand breaks [60], [61]. Therefore, it would be interesting to examine the implication of RPA binding to sites of DNA damage during bleomycin-induced over-replication. In conclusion, our results show that the ATM/ATR pathway plays a crucial role in bleomycin-induced over-replication. Generally, the G2 checkpoint on the ATM/ATR pathway allows cells time to repair DNA damage before cell cycle progression is resumed, thereby contributing to genomic integrity [62]. We found that bleomycin-induced over-replication in HeLa (inactivated p53 by E6 expression) and A431 (mutated p53), and HCT116 (wild-type p53), suggesting that bleomycin-induced over-replication is independent on p53 status. If a sustained G2 checkpoint produces over-replicated cells with wild-type p53, such cells are usually eliminated by the p53-dependent pathway [63]. However, in many cancer cells where p53 is inactivated, the ATM/ATR pathway activated by DNA damage may be involved in SynaptoRedTM C2 through an induction of over-replication. Our results also show that abrogation of the G2 checkpoint by inhibitors of the ATM/ATR pathway suppresses over-replication, and in turn promotes cell death. This suggests that chemotherapy using a combination of bleomycin and inhibitors of the ATM/ATR pathway suppresses ATM/ATR pathway-induced over-replication, and enables us to decrease concentrations of bleomycin. It is of interest to examine the effects on genomic stability of chemotherapy employing combinations of bleomycin and inhibitors of the ATM/ATR pathway.
    Acknowledgments
    Introduction Esophageal carcinoma (EC) is the 8th most common cancer worldwide [1]. EC ranks as the 6th most common cause of cancer-related morbidity and the 4th most common cause of cancer-related mortality in China [2]. EC comprises the following two major pathological types: adenocarcinoma and squamous cell carcinoma. The majority of ESCC cases occur in Asia, particularly in north China. Surgery is known as the main treatment for ESCC, but long-term survival of patients with advanced disease remains poor and unsatisfactory. Currently, the development of comprehensive perioperative therapies has greatly improved the efficacy of ESCC treatment, especially for long-term survival. Platinum-based combination regimen is used most frequently in the clinical practice; however, previous studies have demonstrated that the improved efficacy associated with neoadjuvant therapy is limited to patients who respond to chemotherapy, and the prognosis of non-responders is worse compared with that of patients who received surgery alone [3,4], probably because of chemotherapy resistance, which is inevitable. Thus, new approaches to conquering chemoresistance to improve chemotherapy effectiveness are urgently needed. Platinum-based drugs cross-link with double-stranded DNA and form DNA-platinum abduct to induce DNA damage, leading to cell apoptosis [5]. Due to the intrinsic DDR mechanism, the DNA damage could be repaired. DDR initiation relies on the activation of two major kinase systems, namely, ATR/CHK1 and ATM/CHK2 pathways. Sequentially activated ATR and ATM directly phosphorylate the kinases CHK1 and CHK2, respectively, to activate the downstream effectors such as p53 to upregulate cell cycle checkpoint pathways and then repair the DNA damage [6]. Therefore, DDR is an important chemoresistance mechanism through which tumor cells escape from DNA damage induced by genotoxic agents and thus avoid cell death [[7], [8], [9], [10]]. It has been reported that many malignant cancers are characterized by the functional loss or deficiencies in key proteins involved in the DDR, most notably ATM and p53 [5,6,[11], [12], [13], [14]]. ATM or p53 deficiency in cells leads to synthetic lethality in the presence of ATR depletion [[15], [16], [17], [18], [19]]. Therefore, ATR blockades are considered as promising therapeutic targets, as ATR inhibition may have deleterious effects on cancer cells.