Replication stress and cancer: It takes two to tango

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 tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication

“…While loss of p53 deregulates the cell cycle to enter S phase (5), several laboratories have demonstrated that GOF p53 accelerates cell proliferation and tumor growth in comparison promoters of genes encoding cyclin A (CCNA2), needed for origin firing (19)(20)(21), and CHK1, needed for preventing collapse of replication forks (22)(23)(24), and activates their expression in a cell cycledependent manner at the level of transcription.…”

“…Hyperreplicative activities of oncogenes induce cellular checkpoint responses (31,32) to prevent collapse of progressing replication forks and thus cell death (22,24,33,34). Intra-S phase CHK1 is known to protect replication forks, while inactivation of CHK1 leads to fork collapse, which could be evidenced by phosphorylation of γH2AX (22,24,33). S phase and DNA-replicating cells were identified by PI staining or BrdU pulse labeling and PI staining followed by flow cytometry.…”

“…GOF p53 induces micronuclei formation, which can be prevented by blocking origin firing. Increased frequency of origin firing has been implicated in genomic abnormality (22,24,(37)(38)(39)(40), and one of the indicators of genomic abnormality is micronuclei formation (41)(42)(43). Although an increase in CHK1 levels would protect collapse of replication forks stalled due to increased origin firing, it has been reported that the topological stress associated with progress of an increased number of replication forks may lead to genome abnormality by mechanisms such as fork reversal, which could be evidenced by micronuclei formation (39,40).…”

IncreasedRrm2gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice

“…Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.Supplemental material is available for this article.Received December 5, 2014; revised version accepted March 2, 2015.Replication stress (RS) has emerged as a source of genome instability in human diseases, including cancer and premature aging (Lecona and Fernandez-Capetillo 2014;Zeman and Cimprich 2014). In brief, RS is defined by the accumulation of abnormal amounts of ssDNA at stalled replication forks that, due to its recombinogenic nature, can initiate genomic rearrangements.…”

“…Replication stress (RS) has emerged as a source of genome instability in human diseases, including cancer and premature aging (Lecona and Fernandez-Capetillo 2014;Zeman and Cimprich 2014). In brief, RS is defined by the accumulation of abnormal amounts of ssDNA at stalled replication forks that, due to its recombinogenic nature, can initiate genomic rearrangements.…”