Scientists discovered hundreds of energy-making enzymes secretly working on human DNA—revealing a hidden “mini-metabolism” inside the nucleus that may shape how cancers survive and respond to treatment.

Scientists have discovered that more than 200 metabolic enzymes are located directly on human DNA. Many of these enzymes are usually responsible for producing cellular energy inside mitochondria. The findings were reported in a new study published today (March 6) in Nature Communications.

Researchers found that different cell types, tissues, and cancers each display their own pattern of metabolic enzymes located within the nucleus and interacting with DNA. This discovery provides the first evidence that human cells possess what researchers describe as a “nuclear metabolic fingerprint.”

Scientists are still working to determine exactly what these enzymes are doing in the nucleus. They may be driving chemical reactions, influencing whether genes are switched on or off, or helping support DNA structure. Regardless of the exact role, the findings offer new insight into how tumors grow, adapt, and develop resistance to treatment.

“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.

Mapping Enzymes Attached to Chromatin

To uncover these patterns, the research team used a technique designed to isolate proteins that are physically attached to chromatin, the form DNA takes inside human cells. Using this approach, they analyzed 44 cancer cell lines along with 10 healthy cell types representing ten different tissues.

Traditionally, scientists have viewed metabolism and genome regulation as largely separate biological systems. The nucleus contains the genome, while metabolic enzymes usually work in the mitochondria and cytoplasm to generate energy for the cell.

Because of this long-standing view, the scale of the discovery came as a surprise. The researchers found that metabolic enzymes appear to play an active role inside the nucleus. About 7% of the proteins attached to chromatin were metabolic enzymes, suggesting that the nucleus may contain its own small-scale metabolic system, described by the researchers as a ‘mini metabolism’.

Unexpected Energy Enzymes in the Nucleus

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

The researchers also observed that the distribution of these enzymes varies depending on the type of cancer. For instance, enzymes associated with oxidative phosphorylation were frequently found in breast cancer cells but were largely missing from lung cancer cells. When the scientists examined tumor samples taken from patients, they saw the same pattern, confirming that nuclear metabolism differs 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 Gather at Damaged DNA

To better understand the role of these enzymes, the researchers conducted experiments focused on a group of enzymes that produce the molecular building blocks needed for DNA synthesis and repair. They observed that these enzymes move toward chromatin when DNA is damaged, helping support the repair process.

The experiments also showed that an enzyme’s location inside the cell can significantly change its function. One enzyme, called IMPDH2, behaved very differently depending on where it was located. When researchers forced the enzyme to remain inside the nucleus, it helped maintain genome stability. When restricted to the cytoplasm, it instead influenced other cellular pathways.

Implications for Cancer Treatment

The findings raise important questions about how cancer therapies work. Some treatments are designed to disrupt a tumor’s metabolism, while others aim to interfere with DNA repair. If these two systems are more interconnected than scientists previously believed, the discovery could reshape how researchers think about cancer treatment strategies.

“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.

A Crowded Nuclear Environment

According to the researchers, the study provides the first large-scale evidence that metabolic enzymes are widespread inside the nucleus. Over time, mapping exactly where these enzymes are located and what they do could reveal new biomarkers for diagnosing cancer or uncover new vulnerabilities that future anti-cancer drugs could target.

However, much work remains. Scientists still need to determine whether every enzyme observed in the nucleus is active and what specific role each one plays. “Each enzyme may have its own, unique nuclear function, so this must be addressed one by one,” says Dr. Kourtis.

A Mystery of Cellular Transport

Another unanswered question involves how these enzymes enter the nucleus at all. The nucleus is separated from the rest of the cell by a barrier that normally restricts what molecules can pass through. Many of the enzymes discovered on DNA are much larger than the size that nuclear pores are believed to allow.

Despite this, these large enzymes still manage to enter the nucleus. Researchers suspect that cells may use an as-yet unknown mechanism to bypass these size limits.

Understanding how this transport works could eventually reveal highly precise targets for therapies designed to control nuclear metabolic activity in diseased cells.