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Target: POLD3


Research on POLD3

1. Target Summary:

POLD3 (DNA Polymerase Delta 3) is a critical accessory subunit of the DNA polymerase delta complex, which plays a vital role in DNA replication and repair. It is involved in various cellular processes, including DNA synthesis during replication and the repair of DNA damage. Mutations or deficiencies in POLD3 have been linked to severe immunodeficiency syndromes and various cancers, highlighting its importance in maintaining genomic stability.

2. Mechanism:

POLD3 functions primarily as part of the DNA polymerase delta complex, which is essential for synthesizing DNA during replication and repairing DNA strand breaks. It interacts with other subunits of the polymerase complex, including POLD1 and POLD2, and is crucial for modulating polymerase activity and processivity.
  • DNA Repair: POLD3 is involved in several DNA repair mechanisms, including break-induced replication (BIR) and translesion synthesis (TLS). It helps facilitate DNA synthesis at sites of damage, ensuring the integrity of the genome during replication stress (PMID: 34117478).
  • Replication Stress Response: POLD3 is recruited to sites of DNA damage and is modified by SUMOylation during replication stress, which enhances its activity and stability (PMID: 25497329).
  • Interaction with Other Proteins: POLD3 interacts with proliferating cell nuclear antigen (PCNA), which acts as a sliding clamp to enhance the processivity of DNA polymerases. It also has interactions with other DNA repair proteins, such as RAD52, which is crucial for repairing double-strand breaks (PMID: 31777915).

3. Approved Drugs:

Currently, there are no specific drugs approved that directly target POLD3. However, understanding its role in DNA repair pathways may lead to the development of novel therapeutic strategies targeting POLD3 in cancer treatment.

4. Hypotheses:

  • Cancer Biomarker: POLD3 may serve as a potential biomarker for certain cancers due to its role in DNA repair mechanisms. Its expression levels could correlate with tumor aggressiveness and response to therapy (PMID: 39181133).
  • Therapeutic Target: Targeting POLD3 could enhance the efficacy of cancer therapies that induce DNA damage, as inhibiting its function may sensitize cancer cells to these treatments (PMID: 34117478).
  • Role in Immunodeficiency: Mutations in POLD3 may lead to severe combined immunodeficiency (SCID) and other syndromic conditions, suggesting that its proper function is critical for immune system integrity (PMID: 37030525).

5. Validation:

POLD3 has been validated as a critical component of the DNA polymerase delta complex, with studies demonstrating that mutations in POLD3 lead to significant cellular defects, including impaired DNA repair and increased genomic instability. For instance, a homozygous mutation in POLD3 was identified in a patient with SCID, linking POLD3 deficiency to severe immunological consequences (PMID: 37030525).

6. Clinical Trials:

As of now, there are no specific clinical trials targeting POLD3 directly. However, ongoing research is exploring its role in cancer biology and potential therapeutic implications, which may lead to future clinical trials focused on POLD3 as a target.

7. Involved Pathways:

POLD3 is involved in several key pathways, including:
  • DNA Repair Pathways: Such as homologous recombination and non-homologous end joining.
  • Cell Cycle Regulation: POLD3 plays a role in S-phase progression and the cellular response to replication stress (PMID: 39181133).
  • Fanconi Anemia Pathway: POLD3 is implicated in the repair of interstrand crosslinks and is part of the cellular response to DNA damage (PMID: 34117478).

8. Associated Genes:

POLD3 is part of the DNA polymerase delta complex, which includes:
  • POLD1: The catalytic subunit of the polymerase.
  • POLD2: An accessory subunit that stabilizes the complex.
  • POLD4: Another accessory subunit involved in DNA repair processes.

9. Target Expression:

POLD3 is expressed in various tissues, with its expression levels being particularly relevant in rapidly dividing cells, such as those in the bone marrow and lymphoid tissues. Alterations in POLD3 expression have been observed in various cancers, indicating its potential role in tumor biology (PMID: 39181133).

10. Additional Context:

POLD3's role in DNA repair and replication makes it a critical player in maintaining genomic stability. Its dysfunction can lead to severe immunodeficiencies and contribute to cancer development, making it a significant focus of research in both immunology and oncology.

11. References:

  • PMID: 25497329 - Role of POLD3 in DNA repair and replication stress.
  • PMID: 34117478 - POLD3's involvement in cancer biology.
  • PMID: 37030525 - POLD3 mutations linked to immunodeficiency.
  • PMID: 39181133 - POLD3 as a potential cancer biomarker.
  • PMID: 31777915 - Interaction of POLD3 with RAD52 in DNA repair.
This comprehensive overview of POLD3 highlights its critical functions in DNA replication and repair, its implications in disease, and the potential for future therapeutic targeting.