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

Nature Communications
Julien N BiancoPhilippe Pasero

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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Citations

Dec 22, 2019·Cancers·Camille Franchet, Jean-Sébastien Hoffmann
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Methods Mentioned

BETA
transfection
flow cytometry
surgical resection
transfections
RNA-seq

Software Mentioned

cnvPartition
SAM
R
DESeq2 R
Timeless
GO
FlowJo
STATA
samr
MetaMorph

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