Therapeutic Targeting of DNA Replication Stress in Cancer

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.

Canonical binding of Chaetomium thermophilum DNA polymerase δ/ζ subunit PolD3 and flap endonuclease Fen1 to PCNA

“…In summary, the determination of the structures of Ct PolD3, PolD4 and Fen1 PIP peptides bound to Ct PCNA allows direct comparison of binding modes, both within species (PolD3 versus PolD4 versus Fen1) but also across species, with reference to previously determined structures for human PolD3/p66, PolD4/ p12 and Fen1 PIP peptide-PCNA complexes (Bruning and Shamoo, 2004;Gonzalez-Magana et al, 2019). With increasing interest in the development of inhibitors of PCNA-PIP interactions for therapeutic purposes (Horsfall et al, 2020;Gu et al, 2023), gaining a detailed structural understanding of how these interactions occur, how they have evolved and how this impacts function, is more important than ever.…”