More than 200 metabolic enzymes, many of which are normally responsible for generating energy in mitochondria, are also found directly on top of human DNA, according to research published today. Nature Communications.
This study shows that different types of cells, tissues, and even cancers have unique patterns of metabolic enzymes that are compartmentalized within the nucleus and interact with DNA. This is the first evidence that human cells have what the study authors call a “nuclear metabolic fingerprint.”
More research is needed to determine whether the enzymes catalyze reactions, turn genes on or off, or simply provide structural support, but the study provides new clues about how different types of tumors grow and adapt to or resist treatment.
Many of these enzymes synthesize essential components 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, which is a hallmark of many chemotherapy treatments. It’s a whole new world to explore. ”
Sara Sdelci, Ph.D., corresponding author of this study, Research Scientist, Center for Genome Regulation
The research team made this discovery using a method that isolates proteins that are physically bound to chromatin, the natural state of DNA in human cells. They studied 44 cancer cell lines and 10 types of healthy cells from 10 different tissues.
Metabolism and genomic regulation have traditionally been considered to be generally separate, although sometimes porous, systems. The nucleus hosts the genome, and metabolic enzymes generate energy for the cell in the mitochondria and cytoplasm.
That’s why researchers were surprised by the scale of their discovery, which found that metabolic enzymes appear to be actively involved in nuclear biology. Seven percent of all proteins found attached to chromatin were metabolic enzymes, suggesting that the nucleus has its own independent “mini-metabolism.”
Some enzymes were particularly unexpected. The research team identified that components of oxidative phosphorylation, a process that generates most of a cell’s energy, reside in the human nucleus.
The presence or absence of enzymes and their abundance vary depending on the type of cancer. For example, oxidative kinases are common in breast cancer cells, but almost absent in lung cancer cells. The study authors observed similar patterns when examining tumor samples taken from patients, demonstrating the tissue- and disease-specific nature of nuclear metabolism.
“While we have treated metabolism and genomic regulation as two separate worlds, our study suggests that they are interacting with each other and that cancer cells may exploit these interactions to survive,” said Dr. Sabas Kurtis, lead author of the study.
Researchers conducted experiments to find out what some metabolic enzymes do. They studied a group of enzymes that provide the building blocks for DNA synthesis and repair and found that when DNA is damaged, they cluster around chromatin and help repair the genome.
During these experiments, they discovered that location matters. The enzyme IMPDH2 behaved very differently depending on where it was present. When the researchers forced it to stay only in the nucleus, it helped maintain genome stability, but when confined to the cytoplasm, it instead affects other pathways.
The discovery raised new questions about how cancer treatments work. Some drugs target the metabolic activity of cancer, while others target DNA repair mechanisms. If the two systems are more closely related than previously thought, that has important implications for cancer research.
“This may help explain why tumors of different origins often respond very differently to chemotherapy, radiotherapy, or targeted inhibitors, even when they carry the same mutation,” Dr. Sudersi says.
The study authors say their work is the world’s first evidence of a high concentration of metabolic enzymes within the nucleus. In the long term, mapping the location and function of enzymes could help identify new biomarkers for diagnostics and new vulnerabilities that cancer drugs may exploit.
But to do that, researchers must first determine what each enzyme is doing, or whether all of them are active. “Each enzyme may have its own unique nuclear function, so this needs to be addressed one at a time,” Dr. Courtis says.
Another mystery is how enzymes cross the barrier between the nucleus and cytoplasm in the first place. Many of the enzymes found on DNA are much larger than what is normally thought to be able to pass through nuclear pores, but large, bulky enzymes somehow do.
This raises new questions about what undiscovered mechanisms cells use to circumvent normal size limitations. This line of research may provide highly precise therapeutic targets for controlling nuclear metabolic activity in diseased cells.
sauce:
genome control center
Reference magazines:
Courtis, S. Others. (2026). Native chromatome profiling reveals hundreds of metabolic enzymes in the core throughout tissues. Nature Communications. DOI: 10.1038/s41467-026-69217-2. https://www.nature.com/articles/s41467-026-69217-2
