Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner.
Adaptor Proteins, Signal Transducing
/ biosynthesis
Adenocarcinoma of Lung
/ genetics
Ataxia Telangiectasia Mutated Proteins
/ metabolism
Breast Neoplasms
/ genetics
Cell Cycle Proteins
/ biosynthesis
Cell Line, Tumor
Checkpoint Kinase 1
/ metabolism
Colorectal Neoplasms
/ genetics
DNA Damage
/ genetics
Genomic Instability
/ genetics
HCT116 Cells
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins
/ biosynthesis
MCF-7 Cells
Stress, Physiological
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 02 2019
22 02 2019
Historique:
received:
20
11
2017
accepted:
05
02
2019
entrez:
24
2
2019
pubmed:
24
2
2019
medline:
4
4
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30796221
doi: 10.1038/s41467-019-08886-8
pii: 10.1038/s41467-019-08886-8
pmc: PMC6385232
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CLSPN protein, human
0
Cell Cycle Proteins
0
Intracellular Signaling Peptides and Proteins
0
TIMELESS protein, human
0
ATR protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
CHEK1 protein, human
EC 2.7.11.1
Checkpoint Kinase 1
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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