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Target: POLD2


Research on POLD2

1. Target Summary:

POLD2 (DNA polymerase delta 2) is an essential accessory 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 is implicated in various cancers and immunodeficiencies. High expression levels of POLD2 have been associated with poor prognosis in multiple cancer types, including glioblastoma and multiple myeloma.

2. Mechanism:

POLD2 is a component of the DNA polymerase delta complex, which is responsible for synthesizing DNA during replication and repairing damaged DNA. The complex consists of the catalytic subunit POLD1 and accessory subunits POLD2, POLD3, and POLD4. POLD2 enhances the stability and activity of the polymerase delta complex, facilitating both leading and lagging strand synthesis during DNA replication.
In the context of DNA repair, POLD2 is involved in the base excision repair (BER) pathway, which corrects single-strand breaks and other minor DNA lesions. It is also implicated in the non-homologous end joining (NHEJ) pathway, which repairs double-strand breaks. The expression of POLD2 is regulated by transcription factors such as E2F1, which binds to its promoter and enhances its transcription, thereby promoting cell proliferation, particularly in cancer cells (PMID: 36119494).

3. Approved Drugs:

Currently, there are no specific drugs approved that directly target POLD2. However, therapies that inhibit DNA repair mechanisms, such as PARP inhibitors (e.g., olaparib), may indirectly affect POLD2's function in cancer cells. These drugs are particularly relevant in cancers with defective DNA repair pathways.

4. Hypotheses:

  1. Prognostic Biomarker: POLD2 is hypothesized to serve as a prognostic biomarker in various cancers, with high expression correlating with poor patient outcomes (PMID: 36861411).
  2. Therapeutic Target: Targeting POLD2 could enhance the efficacy of existing cancer therapies, particularly in tumors exhibiting high levels of POLD2 expression, by sensitizing them to DNA-damaging agents (PMID: 31954770).
  3. Role in Immune Response: POLD2 mutations may lead to impaired immune responses, contributing to immunodeficiencies and affecting T-cell development (PMID: 31449058).

5. Validation:

Numerous studies have validated the role of POLD2 in cancer biology and immunology:
  • Cancer Prognosis: High POLD2 expression has been linked to poor survival rates in glioblastoma and multiple myeloma (PMID: 36861411, PMID: 31954770).
  • Functional Studies: Knockdown of POLD2 in glioblastoma cells has shown to sensitize them to chemotherapy and radiation, confirming its role in DNA repair and cell survival (PMID: 31954770).
  • Immunodeficiency: Germline mutations in POLD2 have been associated with syndromic immunodeficiencies, highlighting its importance in immune function (PMID: 31449058).

6. Clinical Trials:

While specific clinical trials targeting POLD2 are limited, ongoing research is exploring the role of POLD2 in combination with other therapies, particularly in cancers like multiple myeloma and glioblastoma. Studies are investigating the efficacy of PARP inhibitors in patients with high POLD2 expression (PMID: 36861411).

7. Involved Pathways:

POLD2 is primarily involved in:
  • DNA Replication Pathway: Facilitating the synthesis of DNA strands during cell division.
  • Base Excision Repair (BER) Pathway: Correcting single-strand breaks and minor DNA lesions.
  • Non-Homologous End Joining (NHEJ): Repairing double-strand breaks in DNA.

8. Associated Genes:

POLD2 interacts with several other genes and proteins, including:
  • POLD1: The catalytic subunit of the DNA polymerase delta complex.
  • POLD3 and POLD4: Other accessory subunits that stabilize the polymerase complex.
  • E2F1: A transcription factor that regulates POLD2 expression.

9. Target Expression:

POLD2 is expressed in various tissues, with particularly high levels observed in rapidly proliferating tissues and tumors. Its expression is often upregulated in cancer cells, correlating with aggressive tumor behavior and poor prognosis (PMID: 36861411).

10. Additional Context:

POLD2's role in DNA repair makes it a critical player in maintaining genomic stability. Its dysregulation can lead to increased mutation rates, contributing to cancer development and progression. Understanding POLD2's functions and interactions may provide insights into novel therapeutic strategies for cancer treatment and management of immunodeficiencies.

11. References:

  • PMID: 36119494
  • PMID: 36861411
  • PMID: 31954770
  • PMID: 30038717
  • PMID: 31449058
This comprehensive overview of POLD2 highlights its significance in cancer biology and potential as a therapeutic target, emphasizing the need for further research to explore its clinical implications.