Scientists have succeeded in purifying a protein found in bacteria that could reveal new drug targets for inherited breast and ovarian cancers as well as other cancers linked to DNA repair faults. They used Diamond Light Source to solve the structure of the protein. The study is published in the journal Nature.
The team, based at Cancer Research UK’s Paterson Institute within the University of Manchester, are the first to decipher the structure of a protein called PARG – which plays an important role in DNA repair and acts in the same pathway as PARP.
PARP inhibitors have been showing great promise in clinical trials for patients with breast, ovarian and prostate cancers caused by mutations in genes called BRCA1 and BRCA2. They work by blocking the action of PARP – a protein that chemically tags areas of DNA damage to highlight them to the cell’s DNA repair machinery.
Right: Ribbon diagram of PARG
PARG removes these chemical tags after the DNA damage has been repaired. So the researchers believe that, similar to PARP inhibitors, drugs designed to block the action of PARG could be effective in treating cancer.
Lead author Dr Ivan Ahel, based at Cancer Research UK’s Paterson Institute in Manchester, said: “For decades scientists have wanted to find out the structure of PARG, but its large size makes it very hard to produce in the lab. By studying a smaller version of PARG found in bacteria, we’ve been able to create a ‘3D map’ that researchers can use to understand more about how PARG works. The next step will be to investigate whether drugs that block its activity might be an effective way of treating cancers driven by faults in DNA repair genes.”
Dr Julie Sharp, senior science information manager at Cancer Research UK, said: “This discovery shows that bacteria and humans share similarities in the cellular machinery they use to repair damaged DNA. Importantly, knowing the structure of PARG in bacteria could help researchers design targeted treatments that are also effective in cancer patients. We hope this will lead to further treatment options for patients with a range of cancers in the future.”
The team solved the structure of PARG with data collected on Diamond's Macromolecular Crystallography beamline I04. Knowing the structure allowed them to understand how it works as an enzyme. This new knowledge will also potentially guide drug-design studies on the human form of the protein.
The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase
Dea Slade, Mark S. Dunstan, Eva Barkauskaite, Ria Weston, Pierre Lafite, Neil Dixon, Marijan Ahel, David Leys & Ivan Ahel
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