Targeting the 8-oxodG Base Excision Repair Pathway for Cancer Therapy

Abstract

Genomic integrity is critical for cellular homeostasis, preventing the accumulation of mutations that can drive diseases such as cancer. Among the mechanisms safeguarding genomic stability, the Base Excision Repair (BER) pathway plays a pivotal role in counteracting oxidative DNA damage caused by reactive oxygen species. Central to this pathway are enzymes like 8-oxoguanine glycosylase 1 (OGG1), which recognize and excise 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) lesions, thereby initiating a series of repair processes that restore DNA integrity. BER inhibitors have recently been identified as a promising approach in cancer therapy, increasing the sensitivity of cancer cells to radiotherapy and chemotherapy. By exploiting tumor-specific DNA repair dependencies and synthetic lethal interactions, these inhibitors could be used to selectively target cancer cells while sparing normal cells. This review provides a robust reference for scientific researchers, offering an updated perspective on small-molecule inhibitors targeting the 8-oxodG-BER pathway and highlighting their potential role in expanding cancer treatment strategies.

Keywords: 8-oxodG; BER; cancer therapy.

Figure 1

Scheme of 8-oxodG-BER pathway: upon detecting 8-oxodG, OGG1 removes the damaged base and the APE1 endonuclease processes the resulting AP site, generating a single-strand break (SSB) intermediate. If this intermediate is not immediately repaired, PARP1 may recognize and bind to the SSB. However, PARP1 is not essential for accurate repair if the BER pathway is functioning properly. The BER pathway is completed when the DNA polymerase β (POL β) incorporates a single nucleotide, and DNA Ligase 3 (LIG3), along with the scaffold protein XRCC1, seals the nick to complete the repair. If the BER machinery fails to complete ligation, long patch repair is thought to take over.

Figure 2

Schematic representation of the BER pathway, visualized as a balanced framework: damage recognition via DNA glycosylases like OGG1 complements repair synthesis and ligation driven by XRCC1, LIG 3, and POL β. Maintaining balance between these forces is crucial for genome stability, while targeted manipulation, by activating (arrow pointing up) damage recognition and inhibiting (arrow pointing down) the repair synthesis, offers a novel strategy to induce cancer cell death through genomic instability.