The Brief

Researchers at the Centre for Genomic Regulation in Barcelona have found more than 200 metabolic enzymes — many normally associated with energy production in mitochondria — sitting directly on human DNA inside the cell nucleus. The study, published in Nature Communications, shows that these enzymes constitute roughly 7% of all chromatin-bound proteins and form tissue-specific patterns that differ markedly between cancer types, with implications for understanding why genetically similar tumours respond differently to treatment.

The Report

A systematic survey of proteins physically attached to chromatin across 54 human cell types has revealed that the cell nucleus harbours an unexpectedly dense population of metabolic enzymes, many of which were previously thought to operate exclusively in other cellular compartments.

The study, led by first author Savvas Kourtis and corresponding author Sara Sdelci at the Centre for Genomic Regulation in Barcelona, profiled 44 cancer cell lines and 10 healthy cell types drawn from 10 different tissues. Using a proteomic technique designed to isolate proteins bound to DNA in its native chromatin context, the team identified over 200 metabolic enzymes on chromatin — accounting for approximately 7% of all chromatin-associated proteins.

Among the most striking findings was the presence of oxidative phosphorylation enzymes — components of the mitochondrial energy production chain — as regular residents of the nucleus. These enzymes were abundant in breast cancer cells but largely absent in lung cancer cells. When the researchers examined tumour samples taken directly from patients, the same tissue-specific patterns held, confirming that the phenomenon is not an artefact of cell culture.

The team also identified enzymes involved in one-carbon folate metabolism gathering near chromatin during DNA damage events, suggesting a direct role in genome repair. In experiments with the enzyme IMPDH2, which synthesises building blocks for DNA, its behaviour depended entirely on its location: confined to the nucleus, it supported genome stability; confined to the cytoplasm, it influenced different cellular pathways entirely.

“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,” Kourtis said.

Sdelci noted the clinical implications. “It could help explain why tumours of different origins, even when carrying the same mutations, often respond very differently to chemotherapy, radiotherapy, or targeted inhibitors,” she said. Current cancer treatments broadly divide into drugs targeting metabolic activity and drugs targeting DNA repair mechanisms. If the two systems are linked through nuclear enzymes, treatment strategies may need to account for a tumour’s specific nuclear metabolic fingerprint.

Several questions remain open. Whether all 200-plus enzymes are catalytically active in the nucleus, or whether some perform non-canonical structural or regulatory roles, is unclear. The researchers also noted that many of the enzymes detected are larger than the size nuclear pores are believed to permit, suggesting an unknown transport mechanism.

The study builds on the Sdelci lab’s 2024 finding that IMPDH2 controls the DNA damage response by modulating PARP1 activity through nuclear NAD+ levels. The concept of metabolic enzymes “moonlighting” in the nucleus has been documented for individual cases since the 1960s, but this is the first comprehensive mapping across tissues and disease states. The paper was first posted as a preprint in December 2023 and underwent more than two years of peer review before publication.

The Angle

The interesting number in this study is not 200. It is 7%. One in fourteen of every protein physically attached to the machinery of genetic regulation turns out to be a metabolic enzyme that the textbooks placed in a different part of the cell. This is not a curiosity at the margins. It is a significant fraction of the nuclear proteome doing something no one had systematically accounted for.

The clinical question it opens is specific and consequential. Oncology has spent decades building two broadly separate categories of intervention — drugs that attack a tumour’s metabolism and drugs that attack its ability to repair DNA. If those two systems are not separate inside the nucleus, if metabolic enzymes are physically present on chromatin and actively modulating the damage response, then the interaction effects between these drug categories are not side effects to be managed. They are the mechanism. Two patients with the same mutation receiving the same chemotherapy, one responding and one not — that gap has always been attributed to vaguely invoked “tumour heterogeneity.” A tissue-specific nuclear metabolic fingerprint is a more precise address for the same observation.

The transport problem is worth noting on its own terms. Many of the enzymes found on chromatin are physically too large to fit through nuclear pores as currently understood. The cells are moving them in anyway. That is either a measurement error or an undiscovered mechanism — and given that the finding replicates across 54 cell types and patient samples, measurement error is looking increasingly unlikely. The biology of nuclear import, a field that considered itself reasonably settled, may have a substantial gap in it.

What the study ultimately describes is a cell that is less compartmentalised than the diagrams suggest — one where the boundary between energy production and genetic regulation is more permeable than anyone had mapped. The researchers have opened a catalogue. Filling it in — enzyme by enzyme, function by function — is the work of the next decade. The 2024 IMPDH2 paper took one entry and found it controlling DNA repair through a mechanism no one had proposed. There are over 200 entries left.