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Disease and treatment

Major breakthrough in understanding resistance to cancer therapy

The introduction of PARP inhibitors was a major breakthrough in treating breast and ovarian cancer. Unfortunately, some types of cancer develop resistance, so the disease returns. An international research team, led by Danish researchers, has made a groundbreaking discovery of how cells repair their DNA. This may be a key to understanding and counteracting resistance to cancer drugs. The discovery also sheds new light on how our body generates different types of antibodies.

DNA is the blueprint of life, and cells closely guard their DNA to protect against any damage. Failure of these mechanisms can be catastrophic: for example, DNA damage is a leading cause of cancer. Danish researchers, led by Chuna Choudhary and Jiri Lukas, recently discovered a previously unknown protein shield that protects our DNA.

“Understanding the process by which cells repair their damaged DNA is essential to understand how cancer develops and how to treat it. The new research improves our understanding of the DNA repair system and potentially paves the way for improving existing cancer treatments and designing new ones,” says the first author of the study, assistant professor Rajat Gupta from the Novo Nordisk Foundation Center for Protein Research.

The social networks of proteins

DNA in our cells often gets damaged, for example, when cells are exposed to X-rays or when they copy their DNA. Fatal changes to the DNA code can occur if the DNA is not reassembled and repaired correctly.

“Decades of previous research had identified many proteins that are involved in repairing DNA, for example, BRCA1 that is functionally defective in many breast cancer patients. However, due to technological challenges, until now not all players involved in the DNA repair game were known.”

The researchers therefore used advanced mass spectrometry technique to get a complete picture of the DNA repair. They monitored “interaction networks” of key proteins involved in repairing DNA.

“This is very similar to using social media, such as Facebook, for finding out interactions of a person. By analysing social network profile of a person we can find links to the individuals he/she interacts with, but who are unknown to us.”

Understanding resistance to cancer drugs

This sophisticated analysis of “social networks of DNA repair” allowed the researchers to discover three previously unrecognized proteins that form a new protein complex, which they call shieldin. When DNA is broken, it needs to protected and be kept intact until it is repaired. If DNA breaks remain exposed, they will be slowly chopped by the nucleases that act as “swords.

“What the shieldin does is act as a molecular ‘shield’ to protect broken DNA ends against the nuclease ‘swords’, and by doing so it aids in DNA repair,” adds professor Chuna Choudhary, who led the research project at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

A fault in the BRCA1 gene increases the risk of breast cancer so significantly that many women, such as the actress Angelina Jolie, have chosen to undergo preventive mastectomy to avoid getting breast cancer. Fortunately, a new class of drugs, called PARP inhibitors, is highly effective in treating people with breast and ovarian cancer who have a faulty BRCA1 gene.

“However, in some patients the drug is not effective, and in other cases patients become resistant to the drug after a period of treatment. The new study reveals interesting links between shieldin and cancer.”

The results show that removing any of the new shieldin proteins makes BRCA1-defective tumour cells resistant to PARP inhibitors.

“Our results provide interesting new insights into how BRCA1-faulty tumours can develop resistance to PARP inhibitors. Understanding these mechanisms will aid in deciding which patients may benefit from the treatment and designing potential new therapies for patients who develop resistance to these drugs.”

A decisive evolutionary step

Interestingly, the same machinery that repairs broken DNA is also used by our immune cells to generate different types of antibodies, which help fight infections. Cells generate different types of antibodies through a process called “class-switching”.

“If we removed shieldin proteins from the cells, they were no longer able to perform the antibody class-switching reactions, so the immune cells could not change from making one type of antibody to another. The immune system therefore loses both flexibility and effectiveness if it lacks shieldin.”

Although further studies are required to elucidate exactly how shieldin influences the development of cancer and the immune system, the researchers think that shieldin may have played a decisive role in the evolutionary leap that resulted in the development of adaptive immune systems, such as those of humans.

“The nurse shark is one of the earliest animals that has an antibody-based adaptive immune system like ours. Strikingly, this shark was the first animal that acquired the shieldin complex, indicating that the emergence of shieldin may have represented a remarkable step in the evolution that allowed the development of an antibody-based advanced immune system in humans.”

DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity” has been published in Cell. The team leader, Chuna Choudhary, is a Professor at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen. The work was carried out in close collaboration with the teams of Jiri Lukas at the Novo Nordisk Foundation Center for Protein Research, Andre Nussenzweig from the United States National Institutes of Health and Michael Lammers from the University of Cologne.

Chuna Choudhary
Professor
We are interested in obtaining novel understanding of the regulatory mechanisms in cell signaling. In particular, we are interested in unraveling the properties and the functional landscape of posttranslational modifications (PTMs) in signaling networks. Our group uses the latest genome editing technologies to generate engineered mammalian cell line models and applies the cutting-edge mass spectrometry-based proteomic technologies for unbiased, global, and quantitative analysis of key regulatory PTMs, including lysine acetylation and ubiquitylation. In this endeavour, the Group collaborates extensively with leading researchers from Denmark and around the world.
Rajat Gupta
Assistant professor
DNA damage presents a major threat to genome stability, and cells have therefore evolved elegant mechanisms, collectively referred to as the DNA damage response (DDR), to protect their genome integrity . We combine CRISPR-based genome editing , APEX-based proximity labeling , and quantitative mass spectrometry to survey protein networks in the neighborhood of the endogenously expressed DDR factors. This allows us to map their interaction landscape in the native environment, revealing new insights into the global DDR networks.