Cancer cells survive by repairing damage to their DNA—even damage that would normally be fatal. One of their most important defense systems is homologous recombination, a high-precision repair pathway that fixes broken DNA using key proteins such as RAD51 and CHK1. While therapies such as PARP inhibitors have successfully targeted this vulnerability, many tumors eventually regain their DNA repair ability and become resistant to treatment.
A research team led by Director MYUNG Kyungjae at the Center for Genomic Integrity within the Institute for Basic Science (IBS), in collaboration with LEE Joo-Yong (Chungnam University) has now uncovered a new strategy to overcome this resistance. Their findings show that cancer cells can be made vulnerable again—not by altering genetic mutations, but by destabilizing the DNA repair machinery itself.
In cells, DNA repair proteins are not static. Their levels are tightly regulated to maintain a balance between repair and genome stability. However, the researchers found that this balance can be deliberately disrupted.
Through a cell-based screening approach designed to identify modulators of replication stress responses, the team discovered a small molecule called UNI418. When applied to cancer cells, UNI418 caused a significant reduction in key DNA repair proteins, including RAD51 and CHK1. As these proteins were depleted, the cells lost their ability to efficiently repair DNA damage.
To understand how this happens, the researchers examined how these proteins are controlled. They found that UNI418 activates a protein degradation system known as the Cul4A ubiquitin ligase complex, which tags specific proteins for destruction. This effectively dismantles the DNA repair system from within.
Co-corresponding author Professor LEE Joo-Yong stated, “We identified a mechanism in which key DNA repair proteins are actively degraded inside the cell. This provides a new way to regulate homologous recombination beyond genetic mutations.”
The team further traced how this degradation pathway is triggered. UNI418 disrupts a signaling pathway involved in inositol phosphate metabolism, reducing the levels of a molecule called IP6. Under normal conditions, IP6 suppresses Cul4A activity. When IP6 levels drop, this suppression is lifted, allowing the degradation system to become active.
As a result, Cul4A—together with its adaptor protein WDR5—targets DNA repair proteins such as RAD51 for degradation, effectively shutting down homologous recombination.
Functionally, this creates a state similar to DNA repair deficiency, even in cancer cells that had previously restored their repair capacity. This finding is particularly important for overcoming resistance to PARP inhibitors, one of the major challenges in current cancer therapy.
The researchers tested whether this approach could improve treatment outcomes. In multiple cell-based experiments, UNI418 significantly increased the sensitivity of cancer cells to PARP inhibitors. Notably, it was also effective in PARP inhibitor-resistant cancer cells, restoring their responsiveness to treatment.
Co-corresponding author Director MYUNG Kyungjae added, “By weakening the DNA repair system, we can re-sensitize tumors that have become resistant to existing therapies. This suggests a new strategy for expanding the effectiveness of PARP inhibitors.”
The team further validated these findings in animal models. In tumor xenograft experiments, UNI418 suppressed tumor growth, particularly when combined with the PARP inhibitor Olaparib. Importantly, this effect was observed even in models that mimic treatment-resistant cancers.
These results indicate that cancer cells remain dependent on DNA repair systems even after developing resistance—and that disrupting protein stability can expose this vulnerability.
Beyond its therapeutic implications, the study also reveals a new biological connection between cellular metabolism and DNA repair. By linking IP6 signaling to the Cul4A-mediated protein degradation pathway, the work uncovers a previously unrecognized mechanism regulating genome stability.
Co-corresponding author Director MYUNG Kyungjae remarked, “This study demonstrates that controlling the stability of DNA repair proteins can directly impact cancer cell survival. It also highlights a new therapeutic direction for overcoming drug resistance.”
Ultimately, the findings suggest that drug-resistant cancers can be made vulnerable again—not by changing their genes, but by dismantling the systems they rely on to repair DNA. Although UNI418 itself will require further development, the mechanism identified in this study provides a promising foundation for next-generation combination therapies.
The study was published in Nature Communications on April 4, 2026.