Researchers from the Novo Nordisk Foundation Center for Protein Research at the Faculty of Health and Medical Sciences have characterised a new protein that is important to the genetic stability of our cells. It may be significant for the development of new drugs against genetically determined diseases like cancer, sterility and premature ageing.

All of our cells contain genetic material, DNA, which controls the activity of the cells. If the genetic material is damaged, cancer cells may develop. Therefore, many proteins and enzymes are responsible for stabilising and protecting our DNA against permanent damage and mutations.

Researchers from the Novo Nordisk Foundation Center for Protein Research at the Faculty of Health and Medical Sciences, University of Copenhagen, have discovered and characterised a new protein called ZUFSP. There is much indication that the protein plays a key role in ensuring that our genetic material remains stable.

‘The protein ZUFSP had not been characterised before, but appeared to contain certain sequences often found in proteins involved in what is referred to as DNA damage response. In addition, there is much indication that ZUFSP plays a main role in helping the cells maintain genetic stability. If we remove ZUFSP, the cells become genetically unstable’, says Head of Research and Professor Niels Mailand.

Genetic stability plays a main role in various aspects of human health. Though the most obvious example of a disease caused by genetic instability is cancer, it also plays a role in neurodegeneration, immunodeficiency, sterility and too early ageing, among others.

DNA Alarm System

The body’s DNA damage response makes sure that damages to the DNA are repaired correctly. It acts as an alarm system that responds every time a damage or change occurs to the DNA. Among other things, the damage response sends specific molecules with various functions out to the DNA damage. One of these molecules is called ubiquitin. They are connected in chains and can act as a directory signal for the proteins responsible for repairing the damage, but they can also stop cell growth until the damage or error has been repaired.

If it proves impossible to repair extensive DNA damages, the cell is usually programmed to destroy itself. However, due to genetic changes, for example caused by failed DNA repair, cancer cells do not always do so. Instead the cancer cell splits up, creating many new cells, which can potentially develop into a cancer tumour.

The newly discovered protein belongs in a class of enzymes called deubiquitylating enzymes or DUBs. Their function is to remove the ubiquitin chains, once they have done their job.

‘Besides ZUFSP appearing to play a role in genetic stability, we also unexpectedly discovered that ZUFSP is a DUB capable of removing a specific type of ubiquitin chain. This type of ubiquitin chain is found in the area around DNA damages and attracts important repair proteins to the damage’, says Head of Research and Professor Niels Mailand.

There are six known DUB classes. The newly discovered ZUFSP does not fit into any of these classes and therefore defines its own seventh class.

The researchers still do not know exactly why it is important for ZUFSP to remove the ubiquitin chains from the area around DNA damages. It is their impression, though, that balance plays a main role with regard to repairing DNA damages. In case of imbalance between the proteins that attach the chains and the ones that remove them again, the proteins do not perform the repair as well as when they are in balance.

Unknown Function in DNA Repair Response

When the researchers first discovered the uncharacterised ZUFSP, they observed that it to a large extent behaved like other proteins involved in DNA repair. A lot of these proteins accumulate physically around DNA damages. This is also the case for ZUFSP.

‘When we wish to examine whether a protein like ZUFSP plays a role in DNA damage response, we can for example choose to attach a small marker to the protein called “green fluorescent protein.” It glows green in the microscope. If we then induce DNA damage to a cell, we can see that ZUFSP, now glowing green, physically moves towards the DNA damage’, says Head of Research and Professor Niels Mailand.

ZUFSP’s movement towards DNA damage suggests that the protein, in addition to removing ubiquitin chains, also in a wide sense plays a role in DNA damage response. So far the researchers do not know exactly what that role is.

Great Potential Within Drug Development

Even though a lot of questions still need answering, the discovery of ZUFSP is significant.

‘This is a very basic discovery. Right now we know what ZUFSP is and what it can do. Now we must try to understand what is happening at the molecular level and its possible biological relevance to pathogenesis’, says Head of Research and Professor Niels Mailand.

Precisely with regard to disease, ZUFSP and other DUBs may come to make a huge difference a couple of years into the future.

‘There is a lot of focus on drug discovery on these DUBs. It is a new pioneer area with promising potential when it comes to developing cancer treatments and other drugs’, he says.

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