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Nat Commun. 2019 Feb 22;10(1):910. doi: 10.1038/s41467-019-08886-8.

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

Author information

1
Institut de Génétique Humaine, CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer, 34396, Montpellier, France.
2
Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany.
3
Cancer Research Center of Toulouse, INSERM U1037, CNRS ERL5294, University of Toulouse 3, 31037, Toulouse, France.
4
Clinical trials Office - Biostatistics Unit, Institute Claudius Regaud, Institute Universitaire du Cancer Toulouse-Oncopole (IUCT-O), 31100, Toulouse, France.
5
Thoracic Oncology Department, Toulouse University Hospital, University Paul Sabatier, 31062, Toulouse, France.
6
Gustave Roussy Cancer Campus, 94805, Villejuif, France.
7
The Institute of Cancer Research, London, SW3 6JB, UK.
8
Institut de Génétique Humaine, CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer, 34396, Montpellier, France. helene.tourriere@igh.cnrs.fr.
9
Institut de Génétique Humaine, CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer, 34396, Montpellier, France. philippe.pasero@igh.cnrs.fr.

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.

PMID:
30796221
PMCID:
PMC6385232
DOI:
10.1038/s41467-019-08886-8
[Indexed for MEDLINE]
Free PMC Article

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