The study shows that different cell types, tissues, and cancers each display their own distinctive arrangement of metabolic enzymes within the nucleus. These enzymes interact with DNA in patterns that researchers describe as a “nuclear metabolic fingerprint,” marking the first evidence that human cells may carry such unique nuclear signatures.

Scientists still need to determine the precise role these enzymes play in the nucleus. They could be driving chemical reactions, influencing whether genes are switched on or off, or contributing to structural support. Even so, the findings already provide new insights into how tumors develop, adapt, and sometimes resist therapy.

“Many of these enzymes synthesize essential building blocks of life, and their nuclear localization is associated with DNA repair. Their presence in the nucleus may therefore directly shape how cancer cells respond to genotoxic stress, a hallmark of many chemotherapeutic treatments. It’s an entirely new world to explore,” says Dr. Sara Sdelci, corresponding author of the study and researcher at the Centre for Genomic Regulation.

Studying Proteins Bound to Chromatin

To identify these enzymes, the research team used a technique that isolates proteins physically attached to chromatin, the natural packaging of DNA in human cells. Using this approach, they examined 44 cancer cell lines and 10 healthy cell types collected from ten different tissues.

Metabolism and genome regulation have traditionally been viewed as largely separate biological systems. The nucleus houses the genome, while metabolic enzymes normally produce energy in mitochondria and the cytoplasm.

Because of this assumption, the scale of the discovery surprised the researchers. They found that metabolic enzymes appear to play active roles in nuclear biology. About 7 percent of all proteins attached to chromatin turned out to be metabolic enzymes. This observation suggests that the nucleus may operate its own small metabolic network described by the researchers as a ‘mini metabolism’.

Unexpected Energy Pathways Inside the Nucleus

Some of the enzymes detected were particularly surprising. The team identified proteins involved in oxidative phosphorylation, the cellular process responsible for generating most of a cell’s energy, as regular occupants of the nucleus.

The pattern of these enzymes also varied depending on cancer type. Oxidative phosphorylation enzymes were commonly observed in breast cancer cells but were largely missing in lung cancer cells. When scientists examined tumor samples taken directly from patients, they observed the same trend, confirming that nuclear metabolism varies depending on tissue type and disease.

“We’ve been treating metabolism and genome regulation as two separate universes, but our work suggests they’re talking to each other, and cancer cells might be exploiting these conversations to survive,” says Dr. Savvas Kourtis, first author of the study.

Enzymes Move to Damaged DNA

The researchers also performed experiments to understand what these nuclear enzymes actually do. They focused on a group of enzymes responsible for producing molecules needed for DNA synthesis and repair.

Their experiments showed that these enzymes gather near chromatin when DNA damage occurs. By concentrating in these regions, they appear to assist with repairing the genome.

The team also discovered that the function of an enzyme can depend on its location inside the cell. One enzyme, called IMPDH2, behaved differently depending on where it was located. When researchers forced it to remain inside the nucleus, it helped maintain genome stability. When the same enzyme was restricted to the cytoplasm, it influenced entirely different cellular pathways.

Implications for Cancer Treatment

These findings raise important questions about how cancer treatments work. Some therapies target metabolic processes in cancer cells, while others focus on disrupting DNA repair systems. If these two biological processes are more tightly connected than previously thought, it could change how scientists approach cancer treatment.

“It could help explain why tumors of different origins, even when carrying the same mutations, often respond very differently to chemotherapy, radiotherapy, or targeted inhibitors,” says Dr. Sdelci.

Mapping Nuclear Metabolism

According to the researchers, this study provides the first large scale evidence that metabolic enzymes are widely present inside the nucleus. Over time, mapping where these enzymes are located and understanding their functions could help identify biomarkers for diagnosing cancer or reveal new weaknesses that anti cancer drugs could target.

However, researchers emphasize that much work remains. Scientists still need to determine whether all of the enzymes observed in the nucleus are active and what specific roles each one plays.

“Each enzyme may have its own, unique nuclear function, so this must be addressed one by one,” says Dr. Kourtis.

How Large Enzymes Enter the Nucleus

Another unanswered question involves how these enzymes reach the nucleus in the first place. The nucleus is separated from the cytoplasm by a barrier that normally limits which molecules can pass through nuclear pores.

Many of the enzymes discovered on DNA are significantly larger than the size these pores are believed to allow. Despite this, the bulky proteins still manage to enter the nucleus.

This puzzling observation suggests that cells may use an as yet unknown mechanism to move large enzymes into the nucleus. Understanding how this process works could eventually reveal precise therapeutic targets for controlling nuclear metabolic activity in diseased cells.