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 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.

Figure 1. Replication Stress and Cancer.

Each S-phase, the replication machinery encounters different roadblocks and cells have specific systems to deal with each of them (left). Some of these alterations remain unresolved through G2 and into mitosis, generating DNA bridges during segregation. Under normal conditions the dissolution and resolution pathways take care of these joint DNA molecules (JM) during G2-Mitosis (centre, top), allowing for the completion of cell division (right, top). In the presence of oncogenes or when some of the mechanisms of repair are mutated or lost, the accumulation of JM in mitosis is too high (centre, bottom) and alterations are carried on through the cellular division, giving rise to genomic instability and cancer (right, middle). In the context of the high levels of RS that can be found on certain tumors, the inhibition of ATR and/or Chk1 is highly cytotoxic since it leads to (a) further amounts of RS and (b) it facilitates the entry into mitosis with unreplicated loci leading to mitotic catastrophe and cell death (right, bottom).