A new study published in Aging Cell reveals that a well-known enzyme, long known for its involvement with cancer, actually steps into the nucleus to help repair DNA.

This enzyme is Protein Disulphide Isomerase (PDI), known for ensuring proteins fold correctly inside the cell. But researchers from Macquarie University and La Trobe University have uncovered a surprising second role. PDI also helps patch double-stranded DNA breaks, acting like a glue to bind the DNA together.

DNA and aging

Ever since researchers discovered DNA, they realized that damage to it can be extremely dangerous. This is particularly prevalent in cells like neurons — where DNA can’t be easily copied from a sister strand. Yet, DNA gets damaged all the time.

“Just like a cut on your skin needs to heal, the DNA in our cells needs constant repair,” says Dr Shadfar.

“Every day, individual cells suffer thousands of tiny hits to their DNA — from both within our own bodies and from environmental stressors like pollution or UV light. Normally, the body responds quickly. But as we age, these repair mechanisms weaken, allowing damage to build up.”

This accumulation of tiny DNA damage is now considered to be the main contributor to aging and the progression of many age-related diseases. Yet again, the brain is particularly vulnerable.

“Brain cells are especially vulnerable,” Dr Shadfar explains. “Unlike skin or blood cells, they don’t divide or renew — so any damage that builds up in them stays. And if the damage isn’t repaired, it can eventually lead to the death of these critical cells.”

If we could find a way to stop this DNA damage, we could address one of the main aspects of aging. But, of course, that’s a big ‘if’. This is where the new study comes in.

PDI is a genetic Swiss army knife

PDI is typically found in the cytoplasm. This is the gelatinous liquid that fills the inside of a cell. It’s there that it folds protein into their proper shapes. But Shadfar’s team made a surprising discovery: PDI can also move into the nucleus, the control center of the cell. When it’s there, it plays a vital role in repairing double-strand breaks, one of the most dangerous types of DNA damage.

“Until now, we didn’t know why PDI sometimes appeared in the nucleus,” says Dr Shadfar. “For the first time, we’ve shown it acts like a glue or catalyst, helping to repair broken DNA in both dividing and non-dividing cells.”

The team further demonstrated this in both mouse cells and human cancer cells. When PDI was removed, the cells struggled to repair themselves. When PDI was added back in, DNA repair started happening. They even tested it in live zebrafish (a common model animal) finding that PDI helps the animals defend against age-related DNA damage.

This is all the more interesting because PDI also plays a role in cancer.

“PDI is like a double agent,” Dr Shadfar explains. “In healthy cells, it repairs DNA and helps prevent disease. But in cancer, it gets hijacked — it ends up protecting the tumour instead of the body. That’s why understanding it fully is so important.”

Could this help us fight aging?

The implications of this discovery stretch across several fields. First and foremost: aging. Accumulated DNA damage is widely considered a central cause of aging, particularly in neurons, which lack robust DNA repair options. Enhancing repair in neurons without introducing excessive mutations is a holy grail in age-related research.

There’s also relevance for neurodegenerative diseases, which often involve heightened oxidative stress and impaired DNA repair. PDI has been loosely linked to disorders like ALS and Alzheimer’s, but this study provides a possible mechanism: if PDI supports DNA repair, its dysfunction could worsen neural damage.

This study opens the door to developing drugs that modulate PDI’s redox function — either enhancing it in vulnerable neurons or suppressing it in cancer cells. But more research is needed to explore how PDI interacts with other repair proteins and how it chooses when and where to act. We can’t just shove it in and expect it to do magic.

But the research is promising. As our understanding of cellular maintenance deepens, even familiar molecules like PDI are revealing hidden talents — and possibly, new ways to keep our cells younger for longer.

The study was published in Aging Cell.