A multidisciplinary research team at the University of Iowa (UI) is investigating how DNA-repair protein RAD52’s structure and functions could lead to new anti-cancer drugs. M. Ashley Spies, professor in the UI College of Pharmacy, discusses this work and the team’s recent publication in Nature. 

“Each cell in our body has its information stored in a DNA 'library,' which is over six- feet long and consists of more than 6 billion ‘letters,’” explained Spies. 

Transferring this information when cells grow and divide is a slow process, according to Spies. Protein machines ensure DNA duplication occurs smoothly, searching for and repairing more than 200,000 DNA lesions in each cell daily. However, cancer cells grow faster than normal cells, often abandoning some slower checks on information integrity and becoming "addicted" to a narrow set of robust, but often inaccurate, DNA maintenance machines. Identifying and targeting molecular machines that specific cancer cells depend on is a valuable therapeutic strategy, allowing scientists to selectively kill cancer cells while sparing healthy ones. This approach could also reduce the doses and side effects of radiation and chemotherapy. A difficult task in developing modern precision therapies is to identify good protein targets and develop therapies that are specific to them. 

The classic example of a drug class used in cancers that lack the functionality of key tumor suppressors, such as BRCA1 or BRCA2 (a state often called “BRCAness”), is the PARP inhibitor class. These drugs target the PARP1 enzyme and are designed to selectively kill cancer cells that are BRCA-deficient. In the same way, cancer cells with BRCAness are critically dependent on RAD52 for survival — which makes RAD52 a highly sought-after target for small-molecule drugs. 

Pros and Cons of RAD52

“This offers a promising new avenue that could rival or even exceed the potential of targeting PARP1,” said Spies. In contrast to PARP1, however, RAD52 is challenging to target because it performs many supportive, non-essential roles in DNA maintenance, making it unclear which function a drug should disrupt. 

Additionally, unlike PARP1, RAD52 is not an enzyme and lacks the deep structural pockets needed for small-molecule inhibitors, making drug development difficult. An 11-RAD52 ring with a deep, narrow DNA-binding groove spanning the ring circumference represents one of the earlier models, but there is disagreement on what exact shape and architecture human RAD52 assumes. 

In Pursuit of New Cancer Therapeutics

The UI team had recently developed a novel set of drug-like inhibitors of RAD52 (Bhat et al., 2023) based on a partial crystal structure of the protein. In this recent Nature study, the team more deeply explored the detailed architecture and genome-stabilizing mechanism of RAD52, which provides valuable new avenues for the further development of small molecules that specifically disrupt the DNA-binding activity of RAD52. The effort of the three research teams at the UI and the Italian National Institute of Health revealed an unexpected architecture consisting of two RAD52 11-mer rings forming a spool-like arrangement embraced by the branched DNA structures, allowing RAD52 to ‘hug’ and rearrange for protection and restoration. According to Spies, this groundbreaking research provides insights into where the protein could be targeted specifically, allowing for further development of the team’s RAD52 inhibitors.