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 -- zones where the genetic material is so tightly packed that making accurate repairs is especially challenging.

Heterochromatin -- a major focus of Chiolo's research -- is 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 -- a 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 -- and 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 -- either 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.

Men and those who are overweight may be especially vulnerable to the effects of restrictive eating, the findings suggest.

A 'healthy' diet rich in minimally processed foods, fresh fruits and vegetables, whole grains, nuts, seeds, lean proteins and fish, is generally associated with a lower risk of depression, while an 'unhealthy' diet, dominated by ultra-processed foods, refined carbs, saturated fats, processed meats and sweets, is generally associated with a heightened risk, explain the researchers.

But people follow many different types of diet for health or medical reasons, including those that restrict calories or particular nutrients, and it's not clear if these other dietary patterns might be associated with a risk of depressive symptoms, they add.

To explore this further, they drew on 28,525 adult respondents (14,329 women and 14,196 men) to the nationally representative US National Health and Nutrition Examination Survey (NHANES) for the years 2007-18, who had completed the Patient Health Questionnaire-9 (PHQ-9) for depressive symptom severity.

In all, 2508 people (just under 8%) reported depressive symptoms, and 7995 participants (29%) had a healthy weight; 9470 (33%) were overweight; and 11060 (38%) were obese.

Participants were asked if they were following any particular diet either to lose weight or for other health reasons, and if so, which of the 9 diet options set out in all 6 cycles of NHANES they were on.

Dietary patterns were categorised into 4 groups: (1) calorie-restrictive; (2) nutrient-restrictive (low in fat/cholesterol, sugar, salt, fibre, or carbs); (3) established dietary patterns (adapted for diabetes, for example); and (4) not on a diet.

Most participants (25,009, 87%) said they weren't on any specific diet, while 2026 (8%) followed a calorie-restrictive diet, 859 (3%) a nutrient-restrictive diet, and 631 (2%) an established dietary pattern.

When stratified by sex, a greater proportion of men (12,772; 90%) than women (12,237; 85%) said they weren't on a diet. Calorie restriction was most commonly reported by obese participants (1247;12%) and those who were overweight (594; 8%), while nutrient-restrictive and established dietary patterns were less commonly reported, with the highest proportion of established dietary pattern users among obese participants (359; 3%).

PHQ-9 scores were 0.29 points higher in those on calorie-restrictive diets than in those not on any specific diet.

The scores were higher among those who were overweight and following a calorie-restrictive diet: their PHQ-9 scores were 0.46 points higher, while a nutrient-restrictive diet was associated with a 0.61 point increase in PHQ-9 scores.

Calorie-restrictive diets were also associated with higher cognitive-affective symptom scores (measure of relationship between thoughts and feelings) while nutrient-restrictive diets were associated with higher somatic symptom scores (excessive distress and anxiety about physical symptoms).

These scores also varied by sex: a nutrient-restrictive diet was associated with higher cognitive-affective symptom scores in men than in women not on a diet, while all 3 types of diet were associated with higher somatic symptom scores in men.

And people living with obesity following an established dietary pattern had higher cognitive-affective and somatic symptom scores than those of a healthy weight not on a diet.

This is an observational study, and as such no firm conclusions can be drawn about causality. Respondents may not have accurately classified their diets either, say the researchers.

The findings also contradict those of previously published studies suggesting that low calorie diets improve depressive symptoms. But the researchers explain: "This discrepancy may arise because prior studies were primarily randomised controlled trials (RCTs) where participants adhered to carefully designed diets ensuring balanced nutrient intake.

"In contrast, real-life calorie-restricted diets and obesity often result in nutritional deficiencies (particularly in protein, essential vitamins/minerals) and induce physiological stress, which can exacerbate depressive symptomatology including cognitive-affective symptoms." Another possible explanation might be a failure to lose weight or weight cycling -- losing weight and then putting it back on, they suggest.

By way of an explanation for the observed gender discrepancies, the researchers point out that glucose and the fatty acid omega-3 are critical for brain health. "Diets low in carbohydrates (glucose) or fats (omega-3s) may theoretically worsen brain function and exacerbate cognitive-affective symptoms, especially in men with greater nutritional needs," they suggest.

Professor Sumantra Ray, Chief Scientist and Executive Director of the NNEdPro Global Institute for Food, Nutrition and Health, which co-owns BMJ Nutrition Prevention & Health with BMJ Group, comments: "This study adds to the emerging evidence linking dietary patterns and mental health, raising important questions about whether restrictive diets which are low in nutrients considered beneficial for cognitive health, such as omega-3 fatty acids and vitamin B12, may precipitate depressive symptoms.

"But the effect sizes are small, with further statistical limitations limiting the generalisability of the findings. Further well designed studies that accurately capture dietary intake and minimise the impact of chance and confounding are needed to continue this important line of inquiry."