Lv Juan, Qian Ying, Ni Xiaoyan, Xu Xiuping, Dong Xuejun
1 Department of Clinical Laboratory Center, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang, P.R. China.
2 Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China.
Tumour Biol. 2017 Mar;39(3):1010428317694307. doi: 10.1177/1010428317694307.
The methyl methanesulfonate and ultraviolet-sensitive gene clone 81 protein is a structure-specific nuclease that plays important roles in DNA replication and repair. Knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 has been found to sensitize cancer cells to chemotherapy. However, the underlying molecular mechanism is not well understood. We found that methyl methanesulfonate and ultraviolet-sensitive gene clone 81 was upregulated and the ATM/Chk2 pathway was activated at the same time when MCF-7 cells were treated with cisplatin. By using lentivirus targeting methyl methanesulfonate and ultraviolet-sensitive gene clone 81 gene, we showed that knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 enhanced cell apoptosis and inhibited cell proliferation in MCF-7 cells under cisplatin treatment. Abrogation of ATM/Chk2 pathway inhibited cell viability in MCF-7 cells in response to cisplatin. Importantly, we revealed that ATM/Chk2 was required for the upregulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 resulted in inactivation of ATM/Chk2 pathway in response to cisplatin. Meanwhile, knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 activated the p53/Bcl-2 pathway in response to cisplatin. These data suggest that the ATM/Chk2 may promote the repair of DNA damage caused by cisplatin by sustaining methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and the double-strand breaks generated by methyl methanesulfonate and ultraviolet-sensitive gene clone 81 may activate the ATM/Chk2 pathway in turn, which provide a novel mechanism of how methyl methanesulfonate and ultraviolet-sensitive gene clone 81 modulates DNA damage response and repair.
甲磺酸甲酯和紫外线敏感基因克隆81蛋白是一种结构特异性核酸酶，在DNA复制和修复中起重要作用。已发现敲低甲磺酸甲酯和紫外线敏感基因克隆81可使癌细胞对化疗敏感。然而，其潜在的分子机制尚不清楚。我们发现，当用顺铂处理MCF-7细胞时，甲磺酸甲酯和紫外线敏感基因克隆81上调，同时ATM/Chk2通路被激活。通过使用靶向甲磺酸甲酯和紫外线敏感基因克隆81基因的慢病毒，我们表明在顺铂处理下，敲低甲磺酸甲酯和紫外线敏感基因克隆81可增强MCF-7细胞的细胞凋亡并抑制细胞增殖。阻断ATM/Chk2通路可抑制MCF-7细胞对顺铂的细胞活力。重要的是，我们发现ATM/Chk2是甲磺酸甲酯和紫外线敏感基因克隆81上调所必需的，敲低甲磺酸甲酯和紫外线敏感基因克隆81会导致顺铂处理下ATM/Chk2通路失活。同时，敲低甲磺酸甲酯和紫外线敏感基因克隆81可激活顺铂处理下的p53/Bcl-2通路。这些数据表明，ATM/Chk2可能通过维持甲磺酸甲酯和紫外线敏感基因克隆81来促进顺铂引起的DNA损伤修复，而甲磺酸甲酯和紫外线敏感基因克隆81产生的双链断裂可能反过来激活ATM/Chk2通路，这为甲磺酸甲酯和紫外线敏感基因克隆81如何调节DNA损伤反应和修复提供了一种新机制。
