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Review
. 2023 Jun 26;14(7):1346.
doi: 10.3390/genes14071346.

Therapeutic Targeting of DNA Replication Stress in Cancer

Long Gu  1 , Robert J Hickey  2 , Linda H Malkas  1
Affiliations
Review

Therapeutic Targeting of DNA Replication Stress in Cancer

Long Gu et al. Genes (Basel). .

Abstract

This article reviews the currently used therapeutic strategies to target DNA replication stress for cancer treatment in the clinic, highlighting their effectiveness and limitations due to toxicity and drug resistance. Cancer cells experience enhanced spontaneous DNA damage due to compromised DNA replication machinery, elevated levels of reactive oxygen species, loss of tumor suppressor genes, and/or constitutive activation of oncogenes. Consequently, these cells are addicted to DNA damage response signaling pathways and repair machinery to maintain genome stability and support survival and proliferation. Chemotherapeutic drugs exploit this genetic instability by inducing additional DNA damage to overwhelm the repair system in cancer cells. However, the clinical use of DNA-damaging agents is limited by their toxicity and drug resistance often arises. To address these issues, the article discusses a potential strategy to target the cancer-associated isoform of proliferating cell nuclear antigen (caPCNA), which plays a central role in the DNA replication and damage response network. Small molecule and peptide agents that specifically target caPCNA can selectively target cancer cells without significant toxicity to normal cells or experimental animals.

Keywords: DNA repair; cancer; chemotherapy; proliferating cell nuclear antigen; replication stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
DNA damaging response signaling pathways [1,2,3,5,6,7,8,9,10,14,15,16,17,19,23,24,25,26,27,28,29]. PLK1: Polo Like Kinase 1; XRCC4: X-Ray Repair Cross Complementing 4; and XLF: XRCC4-like factor.
Figure 2
Figure 2
DNA repair pathways for DSBs and SSBs [4,11,12,13,15,18,20]. formula image RPA and formula image DNA damage. MRN: Mre11/Rad50/Nbs1 complex; 53BP1: p53-binding protein 1; PTIP: Pax transactivation domain-interacting protein; RIF1: Replication Timing Regulatory Factor 1; CtIP: CtBP (carboxy-terminal binding protein) interacting protein; LIGI: DNA ligase 1; LIG3: DNA ligase 3; XRCC4: X-ray Repair Cross Complementing 4; XLF: XRCC4-like factor; APE1: DNA (apurinic/apyrimidinic site) endonuclease 1; Polβ: DNA polymerase β; BARD1: BRCA1 associated RING domain 1; MH: microhomology.
See this image and copyright information in PMC

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