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

被引：104

作者：

Bianco, Julien N. ^{[1
,7
]}

Bergoglio, Valerie ^{[2
]}

Lin, Yea-Lih ^{[1
]}

Pillaire, Marie-Jeanne ^{[2
]}

Schmitz, Anne-Lyne ^{[1
]}

Gilhodes, Julia ^{[3
]}

Lusque, Amelie ^{[3
]}

Mazieres, Julien ^{[4
]}

Lacroix-Triki, Magali ^{[5
]}

Roumeliotis, Theodoros, I ^{[6
]}

Choudhary, Jyoti ^{[6
]}

Moreaux, Jerome ^{[1
]}

Hoffmann, Jean-Sebastien ^{[2
]}

Tourriere, Helene ^{[1
]}

Pasero, Philippe ^{[1
]}

机构：

[1] Univ Montpellier, CNRS, Inst Genet Humaine, Equipe Labellisee Ligue Canc, F-34396 Montpellier, France

[2] Univ Toulouse 3, CNRS ERL5294, INSERM U1037, Canc Res Ctr Toulouse, F-31037 Toulouse, France

[3] IUCT O, Inst Claudius Regaud, Biostat Unit, Clin Trials Off, F-31100 Toulouse, France

[4] Univ Paul Sabatier, Toulouse Univ Hosp, Thorac Oncol Dept, F-31062 Toulouse, France

[5] Gustave Roussy, Canc Campus, F-94805 Villejuif, France

[6] Inst Canc Res, London SW3 6JB, England

[7] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Joseph Stelzmann Str 26, D-50931 Cologne, Germany

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

DNA-DAMAGE RESPONSE; ONCOGENE-INDUCED SENESCENCE; GENOMIC INSTABILITY; FORK PROTECTION; EUKARYOTIC DNA; BREAST-CANCER; UP-REGULATION; LUNG-CANCER; S PHASE; CHK1;

D O I：

10.1038/s41467-019-08886-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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