Targeting the 8-oxodG Base Excision Repair Pathway for Cancer Therapy
<p>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.</p> "> Figure 2
<p>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.</p> ">
Abstract
:1. Introduction
2. Targeting the 8-oxodG-BER Proteins
2.1. OGG1 Inhibitors and Activators
2.2. APE1 Inhibitors
2.3. PARP Inhibitors
2.4. DNA Polymerase β Inhibitors
2.5. Lig/XRCC1 Inhibitors
3. Therapeutic Targeting of the 8-oxodG-BER Pathway: Future Perspectives and Clinical Implications
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Stage of BER Pathway | Inhibitor | Target/Action | Applications |
---|---|---|---|
Recognition of Damage | Inhibits OGG1 binding to 8-oxodG or its enzymatic activity. | Used for inflammatory diseases, fibrosis, and research into oxidative stress mechanisms. | |
Enhances OGG1 activity, shifting dependency to PNKP1 from APE1. | Explored for therapeutic uses in aging and DNA repair enhancement. | ||
APE1 Cleavage of AP Site | Blocks aldehyde sugar recognition at AP sites, preventing APE1 activity. | Enhances chemotherapy efficacy (e.g., TMZ) in cancers; studied in clinical trials (NCTO0692159). | |
Inhibits the redox function of APE1, suppressing tumor growth and transcriptional activity. | Clinical trials in diabetic retinopathy; preclinical cancer studies (NCT03375086). | ||
These new analogs target APE1 function, with APX2009 showing neuroprotective properties against cisplatin-and oxaliplatin-induced toxicity without compromising the antitumor activity of platins. | Potential for furth further development as anti-cancer agents, with neuroprotective applications in chemotherapy. | ||
Targets APE1 endonuclease and redox functions, reducing DNA repair and transcription factor activity. | Synergy with chemotherapeutics was demonstrated in models of lung and pancreatic cancer. | ||
DNA Synthesis (POL β) | Inhibits strand displacement activity of POLβ; induces cell cycle arrest. | Potentiates chemotherapy effects (e.g., TMZ); studied in colorectal cancer. | |
PRO-13 IC50 = 0.4 μM | Irreversibly inhibits POLβ; increases AP sites in alkylation-damaged cells. | Sensitizes cancer cells alkylating agents like MMS. | |
Inhibits POLβstrand displacement and Ligase I activity, impairing BER. | Suppresses cancer cell proliferation, particularly in prostate cancer. | ||
Inhibits POLδ/ε and POLα, impacting long-patch BER. | Studied in chronic lymphocytic leukemia (CLL) and alkylation repair pathways. | ||
Ligation (Ligase 1/3) | Inhibits LIG IV; disrupts XRCC1-LIG 3 complex; leads to DSB accumulation. | Promotes tumor cell apoptosis; studied in BER and NHEJ pathways. | |
Inhibit LIG l and/or LIG IIIα; impair ligation step in BER. | Cytostatic effects in tumor models; selectively affects cancer cells. | ||
PARP Activation | Block ADP-ribosylation, halting DNA repair and trapping PARP-DNA complexes. | Approved for HRR-deficient tumors, including ovarian and prostate cancers. |
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Piscone, A.; Gorini, F.; Ambrosio, S.; Noviello, A.; Scala, G.; Majello, B.; Amente, S. Targeting the 8-oxodG Base Excision Repair Pathway for Cancer Therapy. Cells 2025, 14, 112. https://doi.org/10.3390/cells14020112
Piscone A, Gorini F, Ambrosio S, Noviello A, Scala G, Majello B, Amente S. Targeting the 8-oxodG Base Excision Repair Pathway for Cancer Therapy. Cells. 2025; 14(2):112. https://doi.org/10.3390/cells14020112
Chicago/Turabian StylePiscone, Anna, Francesca Gorini, Susanna Ambrosio, Anna Noviello, Giovanni Scala, Barbara Majello, and Stefano Amente. 2025. "Targeting the 8-oxodG Base Excision Repair Pathway for Cancer Therapy" Cells 14, no. 2: 112. https://doi.org/10.3390/cells14020112
APA StylePiscone, A., Gorini, F., Ambrosio, S., Noviello, A., Scala, G., Majello, B., & Amente, S. (2025). Targeting the 8-oxodG Base Excision Repair Pathway for Cancer Therapy. Cells, 14(2), 112. https://doi.org/10.3390/cells14020112