Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner.
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Date
2019-02-22Author
Bianco, JN
Bergoglio, V
Lin, Y-L
Pillaire, M-J
Schmitz, A-L
Gilhodes, J
Lusque, A
Mazières, J
Lacroix-Triki, M
Roumeliotis, TI
Choudhary, J
Moreaux, J
Hoffmann, J-S
Tourrière, H
Pasero, P
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Cell Line, Tumor
HCT116 Cells
Hela Cells
Humans
Breast Neoplasms
Colorectal Neoplasms
DNA Damage
Genomic Instability
Intracellular Signaling Peptides and Proteins
Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Stress, Physiological
MCF-7 Cells
Ataxia Telangiectasia Mutated Proteins
Checkpoint Kinase 1
Adenocarcinoma of Lung
Language
eng
Date accepted
2019-02-05
License start date
2019-02-22
Citation
Nature communications, 2019, 10 (1), pp. 910 - ?
Publisher
NATURE PUBLISHING GROUP