Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30796221.
- Also identified by DOI 10.1038/s41467-019-08886-8 and PMC identifier 6385232.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Adaptor Proteins, Signal Transducing
- Adenocarcinoma of Lung
- Breast Neoplasms
- Cell Cycle Proteins
- Colorectal Neoplasms
- Intracellular Signaling Peptides and Proteins
- Stress, Physiological