More than two hundred metabolic enzymes, many of which are normally tasked with producing energy in the mitochondria, are also found sitting directly on top of human DNA, according to a study published today in Nature Communications.
The research shows that different cell types, tissues and even cancers each have a unique pattern of metabolic enzymes compartmentalised inside the nucleus and interacting with DNA. It's the first evidence of human cells having what the authors of the study call a "nuclear metabolic fingerprint".
Though further work needs to be done to clarify whether the enzymes are catalysing reactions, turning genes on or off or simply providing structural support, the research provides new clues for how different types of tumours grow, adapt or resist 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.
The team made the discovery by using a method that isolates proteins physically attached to chromatin, the natural state of DNA in human cells. They studied 44 cancer cell lines and 10 healthy cell types from ten different tissues.
Metabolism and genome regulation are traditionally thought to be occasionally porous, but generally separate systems. The nucleus hosts the genome while metabolic enzymes generate energy for cells in the mitochondria and cytoplasm.
That's why the researchers were surprised with the scale of their discovery, which found that metabolic enzymes appear to be active participants in nuclear biology. 7% of all proteins found attached to chromatin were metabolic enzymes, suggesting the nucleus has its own independent 'mini metabolism'.
Some of the enzymes were particularly unexpected. The team identified components of oxidative phosphorylation, the process that generates most of the cell's energy, as regular residents in the human nucleus.
The absence, presence and abundance of the enzymes differed by cancer type. For example, oxidative phosphorylation enzymes were common in breast cancer cells but largely absent in lung cancer cells. When they examined tumour samples from patients, the authors of the study saw a similar pattern, demonstrating the tissue and disease-specific nature of nuclear metabolism.
"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.
The researchers carried out experiments to figure out what some of the metabolic enzymes are doing. They studied one group of enzymes which provide building blocks for DNA synthesis and repair and found they gather around chromatin when DNA is damaged, helping repair the genome.
During these experiments they discovered that location matters. The enzyme IMPDH2 showed completely different behaviour depending on where it was. When the researchers forced it to stay only in the nucleus, it helped maintain genome stability, but when confined to the cytoplasm, it affected other pathways instead.
The discovery raises new questions about how cancer treatments work. Some drugs target a cancer's metabolic activity, while others target its DNA repair mechanisms. If the two systems are more closely linked than previously thought, it has important implications for cancer research.
"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," says Dr. Sdelci.
According to the authors of the study, their research is the first global evidence that the nucleus is crowded with metabolic enzymes. In the long run, mapping the location and function of the enzymes could help identify new biomarkers for diagnosis or new vulnerabilities that anti-cancer drugs could exploit.
But to do that researchers have to first determine what each enzyme is doing or whether all of them are even active. "Each enzyme may have its own, unique nuclear function, so this must be addressed one by one," says Dr. Kourtis.
Another mystery is how enzymes get through the barrier between the nucleus and the cell cytoplasm in the first place. Many of the enzymes found on DNA are far larger than what the nuclear pore is normally thought to allow through, yet enormous bulky enzymes somehow make it through.
That raises new questions about which yet-to-be-discovered mechanism the cell is using to bypass the usual size limits. Following this line of inquiry could in turn lead to very precise therapeutic targets for controlling nuclear metabolic activity in diseased cells.
