logo
    Docs
 

Target: PRIM1


Research on the Target PRIM1

1. Target Summary:

PRIM1 (DNA primase subunit 1) is a crucial enzyme involved in DNA replication, specifically in synthesizing RNA primers necessary for DNA polymerases to initiate DNA synthesis. Mutations in PRIM1 have been linked to various diseases, including primordial dwarfism syndrome and several cancers, such as hepatocellular carcinoma and gastric carcinoma. Its overexpression is often associated with poor prognosis in cancer patients.

2. Mechanism:

PRIM1 functions as a catalytic subunit of the DNA primase complex, which synthesizes short RNA primers during DNA replication. The primase is essential for initiating both leading and lagging strand synthesis.
  • Binding to Replisomes: PRIM1 interacts with the CMG (CDC45-MCM-GINS) helicase complex at replication forks, facilitating the priming of DNA synthesis. This interaction is critical for the coordination of priming activities during DNA replication (Jones et al., 2023, PMID: 37506699).
  • Regulation of Signaling Pathways: In hepatocellular carcinoma (HCC), PRIM1 has been shown to activate the AKT/mTOR signaling pathway, promoting cell proliferation and survival. It also facilitates the ubiquitination and degradation of the tumor suppressor protein P53 via UBE2C, leading to enhanced cell survival and resistance to apoptosis (Zhu et al., 2021, PMID: 33622397).
  • Epithelial-Mesenchymal Transition (EMT): PRIM1 promotes EMT in cancer cells, which is a critical process for cancer metastasis. This transition is associated with increased migratory and invasive capabilities of cancer cells (Zhu et al., 2021, PMID: 33622397).

3. Approved Drugs:

Currently, there are no specific drugs approved that directly target PRIM1. However, therapies that inhibit DNA replication or target the pathways influenced by PRIM1, such as AKT/mTOR inhibitors, may indirectly affect PRIM1's function in cancer cells.

4. Hypotheses:

  • Role in Cancer Progression: It is hypothesized that PRIM1 overexpression contributes to cancer progression by enhancing DNA replication and promoting cell survival through the activation of oncogenic pathways (Zhu et al., 2021, PMID: 33622397).
  • Potential as a Therapeutic Target: Given its role in promoting tumor growth and survival, targeting PRIM1 could be a viable strategy for cancer therapy, particularly in cancers where it is overexpressed (Zhu et al., 2021, PMID: 33622397).
  • Impact on DNA Repair Mechanisms: PRIM1 may also play a role in DNA repair processes, and its dysfunction could lead to genomic instability, further contributing to cancer development (Baranovskiy et al., 2016, PMID: 26710848).

5. Validation:

  • Genetic Studies: Biallelic mutations in PRIM1 have been validated as causative factors in primordial dwarfism syndrome, demonstrating its critical role in human development (Parry et al., 2020, PMID: 33060134).
  • Cancer Correlation: Studies have shown that high levels of PRIM1 expression correlate with poor prognosis in various cancers, including gastric and hepatocellular carcinoma (Guo & Guo, 2023, PMID: 37741096; Zhu et al., 2021, PMID: 33622397).
  • Functional Studies: Loss-of-function studies in cancer cell lines have demonstrated that silencing PRIM1 leads to reduced cell proliferation and increased apoptosis, supporting its role as an oncogene (Zhu et al., 2021, PMID: 33622397).

6. Clinical Trials:

As of now, there are no specific clinical trials targeting PRIM1 directly. However, ongoing research is exploring the implications of targeting DNA replication pathways in cancer therapy, which may include PRIM1 as a potential target.

7. Involved Pathways:

  • AKT/mTOR Pathway: PRIM1 is involved in the activation of the AKT/mTOR signaling pathway, which is crucial for cell growth and survival (Zhu et al., 2021, PMID: 33622397).
  • DNA Replication Pathway: PRIM1 is a key player in the DNA replication pathway, facilitating the synthesis of RNA primers necessary for DNA polymerases (Baranovskiy et al., 2016, PMID: 26710848).

8. Associated Genes:

  • UBE2C: This gene is involved in the ubiquitination of P53, regulated by PRIM1, contributing to cancer cell survival (Zhu et al., 2021, PMID: 33622397).
  • P53: A critical tumor suppressor whose degradation is facilitated by PRIM1 activity, linking PRIM1 to cancer progression (Zhu et al., 2021, PMID: 33622397).

9. Target Expression:

PRIM1 is overexpressed in various cancers, including hepatocellular carcinoma and gastric carcinoma, where its expression levels correlate with poor patient prognosis (Guo & Guo, 2023, PMID: 37741096; Zhu et al., 2021, PMID: 33622397).

10. Additional Context:

PRIM1's role extends beyond cancer; it is essential for normal cellular processes such as DNA replication and repair. Its dysfunction can lead to severe developmental disorders, highlighting its importance in both health and disease.

11. References:

  • Baranovskiy AG, Zhang Y, Suwa Y. Insight into the Human DNA Primase Interaction with Template-Primer. The Journal of Biological Chemistry. 2016; 267(48): 26710848.
  • Guo Z, Guo L. YAP/TEAD-induced PRIM1 contributes to the progression and poor prognosis of gastric carcinoma. Translational Oncology. 2023; 37741096.
  • Jones ML, Aria V, Baris Y. How Pol alpha-primase is targeted to replisomes to prime eukaryotic DNA replication. Molecular Cell. 2023; 37506699.
  • Parry DA, Tamayo-Orrego L, Carroll P. PRIM1 deficiency causes a distinctive primordial dwarfism syndrome. Genes & Development. 2020; 33060134.
  • Zhu M, Wu M, Bian S. DNA primase subunit 1 deteriorated progression of hepatocellular carcinoma by activating AKT/mTOR signaling and UBE2C-mediated P53 ubiquitination. Cell & Bioscience. 2021; 33622397.