Abstract
DNA replication is the fundamental process for accurate duplication and transfer of genetic information. Its fidelity is under constant stress from endogenous and exogenous factors which can cause perturbations that lead to DNA damage and defective replication. This can compromise genomic stability and integrity. Genomic instability is considered as one of the hallmarks of cancer. In normal cells, various checkpoints could either activate DNA repair or induce cell death/senescence. Cancer cells on the other hand potentiate DNA replicative stress, due to defective DNA damage repair mechanism and unchecked growth signaling. Though replicative stress can lead to mutagenesis and tumorigenesis, it can be harnessed paradoxically for cancer treatment. Herein, we review the mechanism and rationale to exploit replication stress for cancer therapy. We discuss both established and new approaches targeting DNA replication stress including chemotherapy, radiation, and small molecule inhibitors targeting pathways including ATR, Chk1, PARP, WEE1, MELK, NAE, TLK etc. Finally, we review combination treatments, biomarkers, and we suggest potential novel methods to target DNA replication stress to treat cancer.
Highlights
Precise, accurate, and error-free DNA duplication of the entire cell genome through DNA replication is necessary for the continuation of controlled, cellular proliferation [1]
DNA replication stress is described as an alteration in error-free DNA replication including a slowdown of DNA synthesis and stalling of replication forks leading to genomic instability [3]
When there is an excess of single-stranded DNA (ssDNA), it depletes available replication protein A (RPA), which causes forks to collapse leading to double-strand DNA break generation [3,9,11,12]
Summary
Accurate, and error-free DNA duplication of the entire cell genome through DNA replication is necessary for the continuation of controlled, cellular proliferation [1]. It is a tightly regulated process comprising a vast number of signaling pathways that ensure that the genome is replicated only once with high fidelity [1]. Because of mutations including oncogenic activation or tumor suppressor gene inactivation, the DDR system may fail to safeguard genomic integrity and fidelity, and DNA replication may persist despite uncorrected DNA errors in response to proliferation signals leading to replication stress [3]. We focus on emerging approaches and propose novel ideas and biomarkers to predict responses
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