AIMP3 and Genome Protection: DNA Repair and Protein Translation

AIMP3 (aminoacyl-tRNA synthetase-interacting multifunctional protein 3) is a key regulator of cellular homeostasis with roles beyond its initial identification in the multi-tRNA synthetase complex. Research has uncovered its involvement in maintaining genome integrity, particularly through DNA repair and stress responses. Given that genomic instability is a hallmark of numerous diseases, including cancer, understanding AIMP3’s functions has significant implications for human health.

Studies highlight AIMP3’s contributions to essential cellular processes under normal and stress conditions. Its interactions with multiple pathways suggest a broader role than previously recognized.

Role In Protein Translation

AIMP3 is a regulatory component of the multi-tRNA synthetase complex (MSC), which aminoacylates tRNAs for protein synthesis. While it does not catalyze aminoacylation, it stabilizes aminoacyl-tRNA synthetases (ARSs) and ensures efficient enzymatic activity. Disruptions in AIMP3 expression reduce translational fidelity, emphasizing its role in protein synthesis accuracy.

Beyond structural support, AIMP3 modulates translation under stress. In adverse conditions such as oxidative stress or nutrient deprivation, it influences ARS activity, adjusting tRNA charging to meet cellular demands. This regulation prevents the accumulation of defective proteins that could impair cell function.

AIMP3 is also involved in translational quality control. It interacts with ribosome-associated surveillance pathways that detect and resolve translation errors. Defective tRNA charging or amino acid misincorporation can produce toxic proteins, and AIMP3 helps coordinate their recognition and resolution. Cells lacking AIMP3 exhibit increased translational errors and protein aggregation, further underscoring its role in maintaining accuracy.

Involvement In DNA Repair Pathways

AIMP3 plays a key role in the DNA damage response (DDR), a network that detects and repairs genomic lesions. Upon DNA damage, AIMP3 is mobilized to mediate interactions between upstream sensors and downstream effectors. It interacts with DDR proteins like ATM and ATR, which regulate checkpoint signaling to pause the cell cycle and allow repair.

AIMP3 is particularly involved in repairing double-strand breaks (DSBs), one of the most severe forms of DNA damage. It enhances homologous recombination (HR), a high-fidelity repair pathway, by facilitating the recruitment of BRCA1 and RAD51. This function is crucial in proliferating cells, where HR prevents mutations that could lead to cancer.

Additionally, AIMP3 contributes to base excision repair (BER), which fixes single-strand breaks (SSBs). It interacts with XRCC1, aiding the recruitment of DNA polymerase β and ligase III to damage sites. This accelerates repair, minimizing persistent DNA nicks that could compromise genome stability. Given BER’s role in repairing oxidative DNA damage, AIMP3’s involvement highlights its protective function.

Contributions To Genome Stability

Genome stability depends on balancing DNA integrity preservation with normal cellular processes. AIMP3 acts as a safeguard against genomic stress, preventing mutations and structural abnormalities linked to aging and disease.

AIMP3 regulates chromatin dynamics, ensuring repair enzymes can access damaged DNA. It interacts with chromatin-modifying complexes, promoting histone modifications that maintain an open chromatin state at repair sites. This enhances repair fidelity and prevents error-prone mechanisms from introducing mutations.

AIMP3 also engages with tumor suppressor pathways, particularly p53, a key regulator of cell cycle checkpoints and apoptosis. Under severe DNA damage, AIMP3 enhances p53 activation, reinforcing the decision to either pause the cell cycle for repair or initiate programmed cell death. This helps prevent the survival of cells carrying harmful mutations.

Observations From Genetic Studies

Genetic studies reinforce AIMP3’s role in genome maintenance. Loss-of-function mutations in AIMP3 correlate with increased genomic instability. Cancer genome analyses reveal reduced AIMP3 expression in breast, lung, and colorectal tumors, suggesting its dysfunction may contribute to oncogenesis. Functional assays show that AIMP3-deficient cells accumulate chromosomal aberrations at a higher rate.

Beyond cancer, genome-wide association studies link AIMP3 polymorphisms to neurodegenerative and age-related diseases. Aging is associated with declining genomic maintenance, and transcriptomic data indicate lower AIMP3 expression in aged tissues, particularly in the brain and liver. CRISPR-based knockdowns of AIMP3 accelerate cellular senescence, reinforcing its role in long-term genomic preservation.