Glutamine Deprivation Triggers Tribbles Homolog 3 Dependent G-Quadruplex Resolution to Maintain DNA Repair and Tumor Survival - PubMed
5 days ago
- #DNA repair
- #Glutamine metabolism
- #Hepatocellular carcinoma
- Glutamine is essential for tumor survival, but therapies targeting glutamine metabolism often fail due to adaptive resistance.
- TRIB3, a pseudokinase, is identified as a key mediator in hepatocellular carcinoma (HCC) cells' adaptation to glutamine deprivation.
- TRIB3 is upregulated under glutamine deprivation in a c-Jun-dependent manner, safeguarding DNA repair fidelity and preventing replication catastrophe.
- TRIB3 binds to G-quadruplex DNA (G4-DNA) structures, recruiting the helicase DDX5 to resolve them, maintaining DNA repair pathways.
- Depletion of TRIB3 or DDX5 leads to G4-DNA accumulation, increased DNA damage, and downregulation of DNA damage repair (DDR) pathways.
- TRIB3-DDX5 prevents G4-DNA accumulation at BRCA1 and RAD51AP1 promoter regions, ensuring transcription of homologous recombination (HR) pathway genes.
- In vivo, TRIB3 silencing suppresses HCC xenograft growth, increasing DNA damage and apoptosis under glutamine-deficient conditions.
- Clinically, TRIB3 overexpression in HCC correlates with poor prognosis, suggesting the TRIB3-DDX5-G4 axis as a therapeutic target.