Suppression of TopBP1 function increases the efficacy of chemotherapeutic treatments by enhancing the induction of apoptosis
Suppression of TopBP1 function increases the efficacy of chemotherapeutic treatments by enhancing the induction of apoptosis
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抑制 TopBP1 功能可通过增强细胞凋亡的诱导来提高化疗的疗效
DOI：
10.1002/osi2.1102
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发表时间：
2021
影响因子：
0.5
通讯作者：
Hidaka Masumi
中科院分区：
文献类型：
--
作者：
Obayashi Yuko;Fujikane Ryosuke;Morita Shou;Uechi Yuka;Hiraki Akimitsu;Hidaka Masumi
DNA损伤反应（DDR）是通过阻止细胞周期进程和诱导DNA修复和/或凋亡来维持基因组完整性的重要机制。因此，DDR的活性与癌细胞的药物敏感性密切相关。ATR是DDR中蛋白激酶的关键成员，ATR抑制剂是化疗增敏剂的有吸引力的候选者。在这项研究中，我们探索了另一种化疗增敏剂的候选者，并报告了DNA拓扑异构酶II结合蛋白1（TopBP 1），一种ATR介导的信号转导调节剂，作为提高化疗疗效的潜在靶点。使用siRNA抑制TopBP 1增加了癌细胞对顺铂和烷化剂N-甲基-N-亚硝基脲（MNU）的敏感性，伴随着亚G1群体和caspase-9活化的百分比增加。免疫印迹分析显示，在TopBP 1-敲低的细胞中，CHK 1的磷酸化显著降低。因此，与ATM抑制剂相比，ATR抑制剂治疗显著增加了亚G1群的产生。在TopBP 1敲低的细胞中，药物处理后RPA 2的磷酸化增加。这些结果表明TopBP 1参与DDR保护停滞的叉免于崩溃，并通过ATR/CHK 1信号通路的激活防止细胞凋亡。
The DNA damage response (DDR) is an important mechanism to maintain genome integrity by arresting cell cycle progression and inducing DNA repair and/or apoptosis. Therefore, the activity of DDR is closely related to the drug sensitivity of cancer cells. Inhibitors of ATR, a key member of protein kinases functioning in DDR, are attractive candidates as sensitizers in chemotherapy. In this study, we explore another candidate of chemosensitizers and report DNA topoisomerase II binding protein 1 (TopBP1), a regulator of ATR‐mediated signaling, as a potential target to increase the efficacy of chemotherapeutic treatments. Suppression ofTopBP1using siRNA increased cancer cell sensitivity to cisplatin and an alkylating agentN‐methyl‐N‐nitrosourea (MNU), concomitant with a percentage increase in the sub‐G1population and caspase‐9 activation. The immunoblotting analysis revealed that the phosphorylation of CHK1 was significantly reduced inTopBP1‐knockdown cells. Consequently, treatment with an ATR inhibitor dramatically increased the production of the sub‐G1population compared to an ATM inhibitor. Phosphorylation of RPA2 increased after drug treatment inTopBP1‐knockdown cells. These results suggest that TopBP1 is involved in DDR protecting stalled forks from collapse and preventing apoptosis through the activation of an ATR/CHK1 signaling pathway.
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影响因子：
16
作者：
Liu S;Shiotani B;Lahiri M;Maréchal A;Tse A;Leung CC;Glover JN;Yang XH;Zou L
通讯作者：
Zou L
影响因子：
158.5
作者：
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通讯作者：
Ryan, G
影响因子：
14.9
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Zuazua-Villar P;Ganesh A;Phear G;Gagou ME;Meuth M
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影响因子：
64.5
作者：
FISHEL, R;LESCOE, MK;KOLODNER, R
通讯作者：
KOLODNER, R
影响因子：
4.7
作者：
Shiraishi, A;Sakumi, K;Sekiguchi, M
通讯作者：
Sekiguchi, M