APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells.
APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells.
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DOI：
10.3389/fcell.2021.738502
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发表时间：
2021
影响因子：
5.5
通讯作者：
Yan S
中科院分区：
文献类型：
--
作者：
Hossain MA;Lin Y;Driscoll G;Li J;McMahon A;Matos J;Zhao H;Tsuchimoto D;Nakabeppu Y;Zhao J;Yan S
维持基因组的完整性和保真度对所有生物体的正常功能和生存至关重要。最近的研究表明，在非洲爪蟾卵提取物中，APE2是激活ATR-Chk1 DNA损伤反应（DDR）途径以响应氧化应激和定义的DNA单链断裂（SSB）所必需的。然而，目前尚不清楚APE2是否是哺乳动物细胞中DDR通路的一般调节因子。在此，我们利用人类胰腺癌细胞提供证据，证明在不同应激条件下，包括氧化应激、DNA复制应激和DNA双链断裂，APE2对ATR - DDR通路激活至关重要。荧光显微镜分析显示，ape2敲低（KD）导致γ - h2ax聚焦增强，微核形成增加。此外，我们发现了一种小分子化合物Celastrol作为APE2抑制剂，它特异性地损害了APE2而不是RPA与ssDNA的结合，以及APE2的3 ‘ -5 ’外切酶活性，而不是APE1。Celastrol在爪蟾卵提取物和人胰腺癌细胞中对ATR-Chk1 DDR通路的损害，凸显了Celastrol在调控APE2基因组完整性功能方面的生理意义。值得注意的是，细胞活力测定表明，APE2-KD或Celastrol使胰腺癌细胞对化疗药物敏感。总的来说，我们认为APE2是DDR通路在基因组完整性维持中的一般调节因子。
The maintenance of genome integrity and fidelity is vital for the proper function and survival of all organisms. Recent studies have revealed that APE2 is required to activate an ATR-Chk1 DNA damage response (DDR) pathway in response to oxidative stress and a defined DNA single-strand break (SSB) in Xenopus laevis egg extracts. However, it remains unclear whether APE2 is a general regulator of the DDR pathway in mammalian cells. Here, we provide evidence using human pancreatic cancer cells that APE2 is essential for ATR DDR pathway activation in response to different stressful conditions including oxidative stress, DNA replication stress, and DNA double-strand breaks. Fluorescence microscopy analysis shows that APE2-knockdown (KD) leads to enhanced γH2AX foci and increased micronuclei formation. In addition, we identified a small molecule compound Celastrol as an APE2 inhibitor that specifically compromises the binding of APE2 but not RPA to ssDNA and 3′-5′ exonuclease activity of APE2 but not APE1. The impairment of ATR-Chk1 DDR pathway by Celastrol in Xenopus egg extracts and human pancreatic cancer cells highlights the physiological significance of Celastrol in the regulation of APE2 functionalities in genome integrity. Notably, cell viability assays demonstrate that APE2-KD or Celastrol sensitizes pancreatic cancer cells to chemotherapy drugs. Overall, we propose APE2 as a general regulator for the DDR pathway in genome integrity maintenance.
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影响因子：
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作者：
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影响因子：
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作者：
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