Zinc-Dependent Proteins Could Hold Key to Cancer and Viral Therapies

In a groundbreaking study published in The Journal of Biological Chemistry, our research team uncovered the molecular mechanism by which zinc-dependent proteins, known as macrodomains, reverse adenosine diphosphate (ADP)-ribosylation—a key regulatory process in cells linked to cancer and viral infections. The multi-institutional study I led from the University of Sheffield, UK, reveals a promising therapeutic pathway, paving the way for targeted drug development against diseases associated with ADP-ribosylation dysfunction.

Untangling protein pathways: A step toward better disease management

The study was driven by the need for more precise approaches in treating diseases that have developed resistance to conventional therapies. As cancer cells and microbial pathogens adapt and exploit cellular processes for survival, researchers are turning to the molecular level to find new therapeutic targets. This research focuses on zinc-dependent macrodomains, proteins that reverse ADP-ribosylation—a cellular modification that helps cells respond to stress. By hijacking these pathways, diseases can enhance their resilience, posing challenges for existing treatments. We aimed to uncover the exact mechanism by which zinc-dependent macrodomains regulate ADP-ribosylation. Understanding this function not only clarifies the role of these macrodomains in cellular health but also presents us with new pathways to create novel targeted therapies to disrupt disease mechanisms.

Decoding protein functions to develop new disease treatments

We examined the role zinc-dependent macrodomains play in reversing ADP-ribosylation, a critical process in cellular regulation and stress response. Using X-ray crystallography, we mapped the active site of these macrodomains to decode how it facilitates the ADP-ribose removal process. Protein assays revealed how zinc ions enable this reaction, while evolutionary comparisons traced the conservation of these enzymes across species, underscoring their biological importance. Additionally, we studied mutations to understand variations in macrodomain function, providing insight into the structure–function relationship. Combined, these experiments create a detailed view of zinc-dependent macrodomains’ molecular activity, underscoring their importance in cellular health and resilience.

The key findings of the paper were:

• Structural analysis showed how macrodomains use zinc ions to hydrolyze ADP-ribose, reversing ADP-ribosylation.
• Zinc ions are essential for the enzymatic activity of these macrodomains.
• Hydrolysis efficiency is directly linked to the role of the zinc ions in the structure of these enzymes.
• Evolutionary studies showed zinc-dependent macrodomains are highly conserved across species.

Paving the way for targeted disease therapies

Our team concluded that zinc is essential in the active site of zinc-dependent macrodomains, enabling them to hydrolyze ADP-ribose from proteins. This critical role explains why these proteins are conserved across species and highlights their importance in cellular stability. Notably, zinc-dependent macrodomains are abundant in pathogens and support cell survival in adverse conditions by helping microbes evade or detoxify reactive oxygen species, making them attractive targets for new antimicrobial treatments. As antibiotic resistance increases, therapies targeting zinc-dependent macrodomains could offer novel ways to combat bacterial and fungal infections.

Understanding the molecular basis for its reversal presents us with further avenues of therapeutic intervention, as this cellular process is also commonly hijacked by cancer cells and viruses to enhance their survival and resistance to treatment. Specifically, the study’s findings suggest that drugs designed to inhibit or modulate the action of these macrodomains could disrupt harmful ADP-ribosylation processes in these disease contexts.

As ADP-ribosylation regulation is better understood, new treatments may emerge, targeting these disease mechanisms. This work thus lays a foundation for translating basic science into therapeutic applications for resistant diseases.

These findings expand our understanding of ADP-ribosylation, a crucial cellular process exploited by cancer cells and viruses. The study confirms the role of ADP-ribosylation in cell resilience and stress response while highlighting the biological relevance of zinc-dependent macrodomains across species. Uncovering the mechanism by which macrodomains remove ADP-ribose from proteins not only provides molecular insights but also identifies potential drug targets. This could inform the design of new therapies to modulate ADP-ribosylation pathways, addressing diseases where this process contributes to pathology.

It is important to note, however, that while this study provides critical insights into zinc-dependent macrodomains and ADP-ribosylation reversal, the in vitro conditions used may not fully reflect the complexity of living organisms. Controlled lab environments, essential for understanding molecular interactions, lack the interacting pathways present in vivo, potentially limiting real-world applicability. Additional research in disease models is necessary to confirm these effects in complex biological systems, as therapeutic applications remain hypothetical until demonstrated in diverse biological contexts.

What’s next for macrodomains in disease treatment?

Future studies will need to explore zinc-dependent macrodomains in more complex disease models. While this study provided foundational insights into how zinc-dependent macrodomains reverse ADP-ribosylation, testing these findings in diverse cellular environments could reveal how other molecular factors influence ADP-ribosylation, helping assess the viability of macrodomains as drug targets. Such research will be crucial to translating these foundational insights into effective therapies.

Reference: Ariza A, Liu Q, Cowieson NP, Ahel I, Filippov DV, Rack JGM. Evolutionary and molecular basis of ADP-ribosylation reversal by zinc-dependent macrodomains. J Biol Chem. 2024;300(10). doi:10.1016/j.jbc.2024.107770

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