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Target: POLD4


Research on POLD4

1. Target Summary:

POLD4 (Polymerase Delta 4) is the smallest subunit of the DNA polymerase delta complex, which plays a critical role in DNA replication and repair. It is involved in maintaining genomic stability and has been implicated in various cancers, including glioblastoma and lung carcinoma. POLD4's expression levels correlate with poor patient prognosis, making it a potential therapeutic target.

2. Mechanism:

POLD4 functions as part of the DNA polymerase delta complex, which is essential for DNA replication and repair. It interacts with other subunits of the polymerase and with the proliferating cell nuclear antigen (PCNA), a sliding clamp that enhances the processivity of DNA polymerases. POLD4 is involved in several key processes:
  • DNA Repair: POLD4 contributes to homologous recombination and the suppression of double-strand breaks (DSBs) during DNA replication. It aids in fork reversal when replication encounters single-strand breaks (SSBs), preventing the formation of DSBs (Kojima et al., 2024).
  • Gene Conversion Regulation: POLD4 has been shown to suppress gene conversion in immunoglobulin-variable genes, indicating its role in regulating homologous recombination (Kojima et al., 2021).
  • Cancer Progression: POLD4 is upregulated in various cancers and is associated with the immune microenvironment, influencing tumor proliferation and response to therapies (Jiang et al., 2023).

3. Approved Drugs:

Currently, there are no specific drugs approved that target POLD4 directly. However, drugs like trametinib, saracatinib, and dasatinib have shown potential efficacy in patients with high POLD4 expression, particularly in glioma (Jiang et al., 2023).

4. Hypotheses:

  • Role in Cancer: POLD4 is hypothesized to play a significant role in cancer progression due to its involvement in DNA repair mechanisms. Its overexpression may contribute to genomic instability and tumorigenesis.
  • Therapeutic Target: Targeting POLD4 could enhance the efficacy of existing cancer therapies by sensitizing cancer cells to DNA-damaging agents, thereby improving treatment outcomes (Fan et al., 2024).

5. Validation:

POLD4's role has been validated through various studies:
  • Knockdown Experiments: Studies have demonstrated that knockdown of POLD4 in glioma cell lines leads to reduced cell proliferation and increased sensitivity to radiation therapy (Jiang et al., 2023).
  • Animal Models: POLD4 knockout mice have shown increased longevity and resistance to tumor formation, suggesting its potential as a target for cancer therapy (Gu et al., 2023).
  • Clinical Correlations: High levels of POLD4 expression correlate with poor survival outcomes in cancer patients, reinforcing its potential as a prognostic biomarker (Alam et al., 2023).

6. Clinical Trials:

While specific clinical trials targeting POLD4 are not yet available, ongoing research is exploring its role in cancer therapies. Future trials may focus on the efficacy of drugs in patients with high POLD4 expression.

7. Involved Pathways:

POLD4 is associated with several critical signaling pathways:
  • DNA Repair Pathways: Involvement in homologous recombination and fork reversal mechanisms.
  • Cell Cycle Regulation: POLD4 expression is linked to cell cycle checkpoints, particularly the G2M checkpoint (Alam et al., 2023).
  • Immune Response Pathways: POLD4's expression correlates with immune cell infiltration and the effectiveness of immunotherapy (Jiang et al., 2023).

8. Associated Genes:

POLD4 interacts with several key genes and proteins:
  • PCNA: A critical cofactor for DNA replication and repair.
  • UCHL3: A deubiquitinating enzyme that stabilizes POLD4 in glioma stem cells (Fan et al., 2024).
  • Other DNA Repair Genes: POLD4 is involved in pathways that include various DNA repair genes, contributing to genomic stability.

9. Target Expression:

POLD4 is significantly upregulated in various cancers, including glioblastoma and lung cancer. Its expression levels correlate with poor prognosis and are associated with tumor recurrence and proliferation (Jiang et al., 2023; Gu et al., 2023).

10. Additional Context:

POLD4's role in cancer biology highlights its potential as a therapeutic target. Understanding its mechanisms and interactions can lead to the development of novel cancer treatments that exploit its functions in DNA repair and replication.

11. References:

  • Gu, X., Dai, Q., & Du, P. (2023). Pold4 is dispensable for mouse development, DNA replication and DNA repair. Gene. PMID: 36356905.
  • Jiang, C., Fan, F., & Xu, W. (2023). POLD4 Promotes Glioma Cell Proliferation and Suppressive Immune Microenvironment: A Pan-Cancer Analysis Integrated with Experimental Validation. International Journal of Molecular Sciences. PMID: 37762224.
  • Kojima, K., Ohkubo, H., & Kawasumi, R. (2024). Pold4 subunit of replicative polymerase delta promotes fork slowing at broken templates. DNA Repair. PMID: 38678695.
  • Kojima, K., Ooka, M., & Abe, T. (2021). Pold4, the fourth subunit of replicative polymerase delta, suppresses gene conversion in the immunoglobulin-variable gene in avian DT40 cells. DNA Repair. PMID: 33588156.
  • Fan, L., You, H., & Jiang, X. (2024). UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells. Cellular and Molecular Life Sciences. PMID: 38829550.
  • Alam, M. T., Ali, M. S., & Goel, H. (2023). Expression Profile, Molecular Association, and Clinical Significance of POLD4 in Glioblastoma. Cellular and Molecular Neurobiology. PMID: 37543966.