Cancer cells can fix the damage that most medicines cause to their DNA. They do this with a very accurate repair system called homologous recombination, which uses proteins like RAD51 and CHK1.
Drugs called PARP inhibitors try to block this repair system. They work well at first, but many tumors find a way around the block and keep growing.
Researchers at the Institute for Basic Science, led by Kyungjae Myung, found a different way to stop the repair system. Instead of changing the DNA, they aimed at the proteins that the cell uses to fix it.
Targeting Repair Proteins
Inside every cell, repair proteins are constantly made and then removed to keep a balance. The team discovered that upsetting this balance can leave cancer cells helpless when their DNA is damaged.
Using a special screen, they found a tiny compound named UNI418. When cancer cells were treated with UNI418, the amount of important repair proteins, such as RAD51 and CHK1, dropped a lot. Without these proteins, the cells could not mend their DNA.
Further tests showed that UNI418 turns on a cellular “trash can” called the Cul4A ubiquitin ligase complex. This trash can tags specific proteins for destruction, breaking apart the DNA‑repair network.
How UNI418 Triggers the Trash Can
UNI418 interferes with a signaling pathway that makes a molecule named IP6. Normally, IP6 keeps the Cul4A trash can under control. When IP6 levels fall, Cul4A becomes more active.
Active Cul4A works together with another protein, WDR5, to tag repair proteins like RAD51 for removal. As these proteins disappear, the cell can no longer perform homologous recombination.
The result looks like a DNA‑repair defect, even in cancers that had repaired themselves before. This could be a key to beating resistance to PARP inhibitors.
Making Old Drugs Work Again
When the scientists added UNI418 to cancer cells that were already resistant to PARP inhibitors, the cells became sensitive once more. The combination worked much better than either drug alone.
In mouse experiments, tumors grew slower when UNI418 was given together with the PARP drug Olaparib. The effect was strongest in tumors that normally ignore PARP inhibitors.
Link Between Metabolism and DNA Repair
The study also revealed a surprising link: a metabolic molecule (IP6) can control how the cell decides to destroy repair proteins. This shows that a cell’s metabolism can directly affect its ability to keep the genome stable.
Although UNI418 still needs more testing, the way it works offers a fresh idea for future cancer therapies: instead of changing the genes, we can knock out the repair machines that let tumors survive.
Published in Nature Communications.