DNA replication stress and cancer chemotherapy

Abstract

DNA replication is one of the fundamental biological processes in which dysregulation can cause genome instability. This instability is one of the hallmarks of cancer and confers genetic diversity during tumorigenesis. Numerous experimental and clinical studies have indicated that most tumors have experienced and overcome the stresses caused by the perturbation of DNA replication, which is also referred to as DNA replication stress (DRS). When we consider therapeutic approaches for tumors, it is important to exploit the differences in DRS between tumor and normal cells. In this review, we introduce the current understanding of DRS in tumors and discuss the underlying mechanism of cancer therapy from the aspect of DRS.

Keywords: DNA damage response; DNA replication stress; chemotherapeutic drugs; genome instability; tumorigenesis.

Figure 1

DNA replication stress. A, Replication fork during normal DNA replication process. Topoisomerases, helicases, DNA polymerases, and dNTP are necessary components for the accurate progression of DNA replication. B‐E, Multiple causes of DNA replication stress. B, dNTP starvation: eg, hydroxyurea induces dNTP starvation by inhibition of ribonucleotide reductase activity. C, Polymerase inhibition: eg, aphidicolin inhibits DNA polymerase activity. D, Inhibition of DNA unwinding by DNA cross‐links, DNA intercalators, or topoisomerase inhibitors. DNA lesions caused by the inhibitors in this category are often converted to DNA strand breaks. E, Inhibition of DNA polymerase progression by DNA adducts: eg, cyclobutane pyrimidine dimer produced by UV light exposure

Figure 2

Destiny of cells that have experienced DNA replication stress. Cells with under‐replicated genomic regions, caused by DNA replication stress during S phase, either activate the DNA damage checkpoint before mitosis or proceed into mitosis. When the DNA damage checkpoint is properly activated, cells cease aberrant growth and induce cellular senescence or apoptosis. As the markers for the DNA damage checkpoint or cellular senescence are often detected in the precancerous lesions, this cascade is believed to constitute a barrier to malignant progression. In contrast, when the DNA damage checkpoint is abrogated, cells with under‐replicated genomic regions proceed into mitosis and induce chromosomal abnormalities, possibly caused by ultrafine bridges (UFBs). These cells display genomic instability, which contribute to malignant progression. ATM, ataxia telangiectasia mutated; Chk2, checkpoint kinase 2

Figure 3

DNA damage response as a result of DNA replication stress. When DNA replication stress is induced, the DNA damage response, governed by the ataxia telangiectasia mutated (ATM) and ATM and Rad3‐related (ATR) kinases, is activated. ATR is activated at the region where single‐stranded DNA is exposed. ATM is also activated in response to DNA replication stress, but in a specific chromatin context. When DNA replication forks collapse and DNA double‐strand breaks are induced, ATM is robustly activated. Both ATM and ATR kinases phosphorylate (represented by P in yellow circle) hundreds of targets that are involved in spreading DNA damage signaling throughout the cell, involving checkpoints for cell cycle progression and activating DNA repair. Checkpoint kinases Chk1 and Chk2 are transducers of DNA damage signaling downstream of ATR and ATM kinase, respectively, and they also phosphorylate multiple targets. p53 is directly phosphorylated by ATM and ATR and functions as a mediator of the DNA damage response