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When DNA breaks inside the cell, it can spell disaster, especially if the damage occurs in areas of the genome that are difficult to repair. Now, scientists Irene Chiolo and Chiara Merigliano at the USC Dornsife College of Letters, Arts and Sciences have discovered that a protein called Nup98, long known for helping traffic molecules in and out of the cell's nucleus, plays another surprising role: guiding the cell's most delicate repairs and reducing the risk of genetic mistakes that can lead to cancer. were published in Molecular Cell.

With support from the National Institutes of Health, the National Science Foundation, and the American Cancer Society, the researchers revealed that Nup98 forms droplet-like structures deep inside the nucleus. These "condensates" act as protective bubbles around broken strands of DNA in areas called heterochromatin鈥攝ones where the genetic material is so tightly packed that making accurate repairs is especially challenging.

Heterochromatin鈥攁 major focus of Chiolo's research鈥攊s filled with repeated DNA sequences, making it easy for the cell to confuse one stretch for another. Nup98's droplets help lift the damaged section out of that dense zone and create a safer space where it can be repaired accurately, reducing the chance of genetic mix-ups that could lead to cancer.

The researchers also found that Nup98 helps mobilize the damaged site in tightly packed heterochromatin, so it can reach a different part of the nucleus where repair is safer.

Coordinating the repair crew

Timing is everything when it comes to DNA repair, and one of Nup98's most important roles is knowing when to say, "Not yet."

The protein's droplet-like condensates act as a temporary shield around damaged DNA, keeping out certain repair proteins that can cause trouble if they arrive too soon. One of those proteins, called Rad51, can accidentally stitch together the wrong pieces of DNA if it gets involved too early in the process.

"The Nup98 droplets keep Rad51 away until other mechanisms have done their work to line up the correct pieces," Chiolo said. "Only once the damaged heterochromatin moves into a different nuclear space, Rad51 can safely finish the repair."

By coordinating this carefully staged process, Nup98 helps cells avoid dangerous genetic rearrangements鈥攁 key part of maintaining genome stability and slowing processes responsible for cancer and aging.

Implications for cancer and therapy

Although the researchers studied cells of fruit flies, the insights gained can help explain how similar DNA repair mechanisms work in humans. Many DNA repair mechanisms in fruit flies are shared across species, making them a powerful model for understanding genome stability.

The Nup98 discovery could have real-world impact, especially for diseases like acute myeloid leukemia, where mutations in Nup98 are known to play a role. By elucidating how Nup98 guides DNA repair, scientists hope to uncover why its mutations are so dangerous鈥攁nd how to harness the mutations to disrupt cancer cells in targeted treatments.

"Eventually, we may also be able to turn Nup98 mutations that lead to cancer, especially acute myeloid leukemia, into treatment targets鈥攅ither by specifically disrupting the cells carrying the mutation or by inactivating the harmful functions of the mutated proteins," Merigliano said.

The team also sees long-term potential for therapies that could enhance or mimic Nup98's protective functions, reducing the risk of genome instability, which is a major factor not only in cancer, but also in aging and other genome instability disorders.

The study was an international effort with 17 scientists from seven institutions collaborating.