Genotoxins exaggerate the stressed state of aneuploid embryonic stem cells via activation of autophagy
Genotoxins exaggerate the stressed state of aneuploid embryonic stem cells via activation of autophagy
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基因毒素通过激活自噬加剧非整倍体胚胎干细胞的应激状态
DOI：
10.1007/s11427-019-9666-y
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
Huang Yue
中科院分区：
文献类型：
--
作者：
Zhang Meili;Xiao Rong;Liu Guang;Huang Yue
非整倍性的细胞后果很大程度上取决于所检查的细胞类型。非整倍体酵母和小鼠胚胎成纤维细胞表现出细胞增殖缺陷，并且可以被引起蛋白毒性或能量应激的化合物选择性抑制。相比之下，大多数非整倍体多能干细胞增殖迅速并达到更高的饱和密度。非整倍体多能干细胞对应激诱导化合物的反应仍不清楚。在这里，我们使用先前建立的 6、8、11 或 15 号染色体三体的小鼠胚胎干细胞系测试了非整倍体胚胎干细胞对几种引起蛋白质毒性、能量和基因毒性应激的化合物的反应。并非所有三体胚胎干细胞都被引起蛋白质毒性或能量应激的化合物选择性抑制。然而，大多数这些细胞表现出对基因毒素的敏感性增加。它们表现出较高的 DNA 损伤反应，其特征是在基因毒性应激下 γH2A.X 病灶增加。进一步的研究表明，自噬水平升高可能导致基因毒素对三体胚胎干细胞的细胞毒性作用增强。我们的研究为消除非整倍性奠定了基础，这可能是控制癌症进展的有效方法。
The cellular consequences of aneuploidy are largely dependent on the cell types examined. Aneuploid yeasts and mouse embryonic fibroblasts exhibit cell proliferation defects and can be selectively inhibited by compounds that cause proteotoxic or energy stress. By contrast, most aneuploid pluripotent stem cells proliferate rapidly and reach higher saturation densities. The responses of aneuploid pluripotent stem cells to the stress-inducing compounds remain uncharacterized. Here, we tested the response of aneuploid embryonic stem cells to several compounds that caused proteotoxic, energy and genotoxic stress using previously established mouse embryonic stem cell lines trisomic for chromosome 6, 8, 11, or 15. Not all trisomic embryonic stem cells were selectively inhibited by compounds that cause proteotoxic or energy stress. However, most of these cells exhibited increased sensitivity to genotoxins. They displayed elevated DNA damage response as characterized by increased γH2A.X foci under genotoxic stress. Further investigations indicated that elevated autophagy levels might contribute to the increased cytotoxic effects of genotoxins on trisomic embryonic stem cells. Our study laid the foundation for eliminating aneuploidy that might be an effective approach for controlling cancer progression.
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
P. Katherine;ster;Justyna L. Pipka;Colby Chiang;Yunxian Liu;Royden A. Clark;R. Keller;P. Skoglund;Michael J. Guertin;Ira M. Hall;P. Stukenberg
通讯作者：
P. Katherine;ster;Justyna L. Pipka;Colby Chiang;Yunxian Liu;Royden A. Clark;R. Keller;P. Skoglund;Michael J. Guertin;Ira M. Hall;P. Stukenberg
影响因子：
5
作者：
Yoshida, Masashi;Shiojima, Ichiro;Komuro, Issei
通讯作者：
Komuro, Issei
影响因子：
9.9
作者：
通讯作者：
--
DOI：
10.1007/s11427-019-9490-8
发表时间：
2019-03
期刊：
Science China Life Sciences
影响因子：
--
作者：
He Shen;Xi Chen;Xing Li;Ke-Rong Jia;Zhifeng Xiao;Jianwu Dai
通讯作者：
He Shen;Xi Chen;Xing Li;Ke-Rong Jia;Zhifeng Xiao;Jianwu Dai
影响因子：
56.9
作者：
Williams, Bret R.;Prabhu, Vineet R.;Amon, Angelika
通讯作者：
Amon, Angelika