Breakthrough in cancer treatment: Study reveals DNA repair protein structure, paving way for targeted cancer drugs

When cancer cells lose one way to repair their DNA, they quickly find another. That workaround often involves RAD52 — a protein now squarely in the sights of researchers hunting for new anti-cancer drugs. A new study published in Nature reveals an unexpected structure adopted by RAD52, providing scientists with valuable insights that could lead to more effective, less toxic cancer treatments.

RAD52 has already shown promise as a drug target. Inhibitors of the protein can selectively kill cancerous cells while sparing healthy ones, reducing the collateral damage typically caused by radiation and chemotherapy. This selective action mirrors the approach used by PARP inhibitors, the first drugs approved to treat BRCA1/2-deficient cancers. While PARP inhibitors like olaparib leave nearly 15% of patients disease-free for over five years, many others develop resistance within the first year.

“RAD52 is a coveted drug target for treating cancers that have DNA repair deficiencies, including breast and ovarian cancers, and some glioblastomas,” said Maria Spies, PhD, senior author of the University of Iowa-led study and professor at the UI Carver College of Medicine.

“This protein is an attractive target for new anti-cancer drugs because while it is dispensable in healthy human cells, RAD52 becomes essential for the survival of cancer cells, which are deficient in DNA repair function, such as those with defects in BRCA1 and BRCA2 genes,” she told phys.org.

Spies emphasised that targeting RAD52 alone or in combination with PARP inhibitors could expand treatment options. But designing effective drugs requires a deeper understanding of RAD52’s molecular behavior.

That’s where the new study comes in. The researchers discovered that RAD52 protects stalled DNA replication forks, a process critical to cancer cell survival. Using high-powered, custom-built microscopes, Spies’s team observed RAD52-DNA interactions at the single-molecule level. What they saw was unexpected: two RAD52 rings attaching to DNA — previously, only single-ring structures had been noted.

“Although the single ring structure had been observed previously, this is the first structure showing the two rings together on the DNA, doing something unexpected,” Spies said. “This new structure provides clues about which important areas of the protein can be targeted for future drug discovery.”

While her team already has small molecules that inhibit RAD52, more refinement is needed to make them viable drugs. “This work and our structure-activity knowledge gained in this study sets up future work on understanding the RAD52 activities and regulation and offers new targets for its inhibition,” Spies said. “Hopefully, this information will help us develop new inhibitors of this protein and tap the potential of RAD52 as an anti-cancer drug target.”