The APE2 Exonuclease Is a Client of the Hsp70-Hsp90 Axis in Yeast and Mammalian Cells.
The APE2 Exonuclease Is a Client of the Hsp70-Hsp90 Axis in Yeast and Mammalian Cells.
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DOI：
10.3390/biom12070864
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发表时间：
2022-06-21
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
分子伴侣如Hsp70和Hsp90有助于折叠和激活重要信号转导途径中的蛋白质，包括DNA损伤反应（DDR）。先前的研究表明，哺乳动物APE 2核酸外切酶（DNA修复的关键蛋白）的水平可能取决于伴侣蛋白的活性。在这项研究中，我们证明了芽殖酵母Apn2核酸外切酶与分子伴侣Ssa1和Hsp82和共伴侣Ydj1相互作用。虽然Apn2不显示对任何特定的胞质Hsp70或Hsp90蛋白的结合偏好，但当作为细胞中唯一的Ssa存在时，Ssa 1不能支持Apn2的稳定性。外切核酸酶APE 2也与哺乳动物细胞中的Hsp70和Hsp90结合，证明了这种机制的保守性。通过特异性小分子抑制剂抑制伴侣蛋白功能导致一系列癌细胞系中APE 2的快速丧失。总之，这些数据确定APE 2和Apn2作为酵母和哺乳动物细胞中伴侣系统的客户，并表明伴侣抑制可能形成靶向APE 2介导过程的新型抗癌疗法的基础。
Molecular chaperones such as Hsp70 and Hsp90 help fold and activate proteins in important signal transduction pathways that include DNA damage response (DDR). Previous studies have suggested that the levels of the mammalian APE2 exonuclease, a protein critical for DNA repair, may be dependent on chaperone activity. In this study, we demonstrate that the budding yeast Apn2 exonuclease interacts with molecular chaperones Ssa1 and Hsp82 and the co-chaperone Ydj1. Although Apn2 does not display a binding preference for any specific cytosolic Hsp70 or Hsp90 paralog, Ssa1 is unable to support Apn2 stability when present as the sole Ssa in the cell. Demonstrating conservation of this mechanism, the exonuclease APE2 also binds to Hsp70 and Hsp90 in mammalian cells. Inhibition of chaperone function via specific small molecule inhibitors results in a rapid loss of APE2 in a range of cancer cell lines. Taken together, these data identify APE2 and Apn2 as clients of the chaperone system in yeast and mammalian cells and suggest that chaperone inhibition may form the basis of novel anticancer therapies that target APE2-mediated processes.
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