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Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner

Abstract : 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.
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https://hal.archives-ouvertes.fr/hal-02047561
Contributor : Catherine Larose <>
Submitted on : Thursday, June 10, 2021 - 10:18:27 AM
Last modification on : Monday, July 5, 2021 - 4:42:04 PM

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Julien Bianco, Valérie Bergoglio, Yea-Lih Lin, Marie-Jeanne Pillaire, Anne-Lyne Schmitz, et al.. Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner. Nature Communications, Nature Publishing Group, 2019, 10 (1), pp.910. ⟨10.1038/s41467-019-08886-8⟩. ⟨hal-02047561⟩

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