Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner
Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner
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DOI：
10.1038/s41467-019-08886-8
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发表时间：
2019-02-22
影响因子：
16.6
通讯作者：
Pasero, Philippe
中科院分区：
文献类型：
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作者：
Bianco, Julien N.;Bergoglio, Valerie;Pasero, Philippe
癌基因诱导的复制应激(RS)促进肿瘤的发展，但也通过激活抗癌屏障来阻碍肿瘤的生长。为了确定癌细胞如何适应RS，我们监测了ATR-CHK1通路的不同组成部分在原发肿瘤样本中的表达。我们表明，与该途径的上游组件不同，检查点调节因子Claspin和Timless以一种协调的方式过度表达。值得注意的是，将HCT116细胞中Claspin和Timless的水平降低到肿瘤前的水平可以阻止分叉进展，而不会影响检查点信号。这些数据表明，高水平的Claspin和Timless通过保护癌细胞中的复制叉来增加RS的耐受性。此外，我们报道了原代成纤维细胞通过自发过表达Claspin和Timless来适应癌基因诱导的RS，而不依赖ATR信号。总之，这些数据表明，Claspin和Timless水平的增强代表了一种功能的获得，该功能以检查点无关的方式保护癌细胞免受癌基因诱导的RS的影响。
Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner.