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Exp Cell Res. 2014 Nov 15;329(1):26-34. doi: 10.1016/j.yexcr.2014.09.019. Epub 2014 Sep 26.

Replication stress and cancer: it takes two to tango.

Author information

1
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain.
2
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain. Electronic address: ofernandez@cnio.es.

Abstract

Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumors with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

KEYWORDS:

ATR; CHK1; Cancer; Replication Stress

PMID:
25257608
PMCID:
PMC4878650
DOI:
10.1016/j.yexcr.2014.09.019
[Indexed for MEDLINE]
Free PMC Article

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