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Target: POLE3


Research on the Target POLE3

1. Target Summary:

POLE3 (DNA polymerase epsilon 3) is an accessory subunit of the DNA polymerase epsilon complex, which plays a critical role in DNA replication and repair. It is involved in maintaining chromatin integrity and has been identified as a transcriptional repressor of unintegrated HIV-1 DNA, crucial for efficient viral integration and evasion from innate immune sensing. Additionally, POLE3 is implicated in various cancers, particularly those with mutations in the POLE gene, and is a potential target for therapeutic interventions.

2. Mechanism:

POLE3 functions primarily as part of the DNA polymerase epsilon complex, which is essential for leading-strand DNA synthesis during replication. It interacts with other subunits, including POLE4, to form a stable polymerase complex that facilitates accurate DNA replication.
In the context of HIV-1, POLE3 acts as a transcriptional repressor by maintaining unintegrated viral DNA in a repressive chromatin state. This prevents the recruitment of RNA polymerase II (RNAPII) to the viral promoter, thereby inhibiting transcription and integration of the viral genome into the host DNA (Thenin-Houssier et al., 2023, PMID: 37922361).
Moreover, POLE3 is involved in DNA damage repair mechanisms, particularly in the repair of double-strand breaks (DSBs). It interacts with various proteins, such as WDR70 and CHRAC1, to facilitate homologous recombination and maintain genomic stability (Mao et al., 2023, PMID: 37682991).

3. Approved Drugs:

Currently, there are no specific drugs approved that directly target POLE3. However, therapies that exploit the vulnerabilities associated with POLE3 mutations, such as PARP inhibitors, are being explored in clinical settings (Hill et al., 2024, PMID: 38753485).

4. Hypotheses:

  1. Therapeutic Targeting: Targeting POLE3 may enhance the efficacy of existing cancer therapies, particularly in tumors with POLE mutations or deficiencies in DNA repair mechanisms.
  2. HIV Treatment: Inhibiting POLE3 could disrupt its role in maintaining a repressive state of unintegrated HIV-1 DNA, potentially leading to increased viral replication and integration, which could be leveraged in therapeutic strategies.
  3. Radiation Sensitivity: POLE3 may play a role in the sensitivity of cancer cells to ionizing radiation, suggesting that its inhibition could sensitize tumors to radiotherapy (CRUK RadNet).

5. Validation:

The role of POLE3 in HIV-1 integration has been validated through experiments demonstrating that its depletion reduces the efficiency of viral integration and replication (Thenin-Houssier et al., 2023, PMID: 37922361). In cancer research, studies have shown that loss of POLE3 sensitizes cells to PARP inhibitors, indicating its involvement in DNA repair pathways (Hill et al., 2024, PMID: 38753485). Additionally, ongoing clinical trials are assessing the impact of POLE mutations on treatment outcomes in various cancers, providing further validation of its significance as a therapeutic target.

6. Clinical Trials:

Several ongoing clinical trials are investigating the role of POLE3 and related pathways in cancer treatment:
  • Phase II Trials: Trials are assessing the efficacy of immunotherapy in patients with POLE-mutated cancers, particularly endometrial cancer (NCT03150706, NCT03435107).
  • Radiation Sensitivity Studies: Research is being conducted to evaluate the role of POLE3 in resistance to ionizing radiation, with the aim of identifying novel therapeutic strategies to enhance sensitivity (CRUK RadNet).

7. Involved Pathways:

POLE3 is involved in several critical pathways:
  • DNA Replication Pathway: As part of the DNA polymerase epsilon complex, POLE3 is essential for leading-strand synthesis during DNA replication.
  • DNA Damage Repair Pathway: POLE3 participates in homologous recombination and other DNA repair mechanisms, interacting with proteins involved in DSB repair.

8. Associated Genes:

  • POLE4: Another subunit of the DNA polymerase epsilon complex that works in conjunction with POLE3.
  • WDR70: A protein that interacts with POLE3 and is involved in the regulation of histone modifications and DNA repair.
  • CHRAC1: A chromatin remodeling factor that interacts with POLE3 to facilitate DNA repair processes.

9. Target Expression:

POLE3 is expressed in various tissues, with higher expression levels observed in rapidly dividing cells, such as those found in tumors. Its expression is crucial for maintaining genomic stability and proper DNA replication.

10. Additional Context:

POLE3 mutations have been associated with various cancers, including endometrial and colorectal cancers. The presence of POLE mutations often correlates with a favorable prognosis, making it a significant focus of ongoing research in oncology. Understanding the role of POLE3 in both cancer and viral biology could lead to novel therapeutic strategies that exploit its functions.

11. References:

  • Thenin-Houssier S, Machida S, Jahan C. POLE3 is a repressor of unintegrated HIV-1 DNA required for efficient virus integration and escape from innate immune sensing. Science Advances. 2023 Nov 3;9(44):eadh3642. PMID: 37922361.
  • Hill BR, Ozgencil M, Buckley-Benbow L. Loss of POLE3-POLE4 unleashes replicative gap accumulation upon treatment with PARP inhibitors. Cell Reports. 2024 May 28. PMID: 38753485.
  • Mao X, Wu J, Zhang Q. Requirement of WDR70 for POLE3-mediated DNA double-strand breaks repair. Science Advances. 2023 Sep 8;9(36):eadh2358. PMID: 37682991.
  • CRUK RadNet. Investigating the role of POLE3 in resistance to ionizing radiation treatment. CRUK RadNet.