More than 200 metabolic enzymes, which are typically known for their role in producing energy within mitochondria, have been found directly on human DNA, according to a study published in Nature Communications. The research identified that different cell types, tissues, and cancers each display a unique arrangement of these metabolic enzymes inside the nucleus, forming what the authors describe as a "nuclear metabolic fingerprint."
The study raises new questions about how tumors grow and respond to treatment. While it is not yet clear whether these enzymes are catalyzing reactions, influencing gene activity, or serving structural roles, the findings suggest a closer relationship between metabolism and genome regulation than previously understood.
Researchers used a method that isolates proteins physically attached to chromatin—the form DNA takes in cells—to analyze 44 cancer cell lines and 10 healthy cell types from various tissues. Traditionally, metabolism and genome regulation have been considered mostly separate processes: the nucleus contains genetic material while metabolic enzymes function mainly in mitochondria and cytoplasm.
However, the researchers were surprised by the extent of overlap. They found that about 7% of all proteins attached to chromatin were metabolic enzymes. This suggests that the nucleus may have its own distinct 'mini metabolism.' Some unexpected findings included components of oxidative phosphorylation—usually responsible for generating most cellular energy—being present in the nucleus.
The presence and abundance of these enzymes varied depending on cancer type. For instance, oxidative phosphorylation enzymes were common in breast cancer cells but largely absent in lung cancer cells. Similar patterns were observed when examining tumor samples from patients, highlighting tissue- and disease-specific 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," said Dr. Savvas Kourtis, first author of the study.
Further experiments showed that some metabolic enzymes play direct roles during DNA damage repair. One group of such enzymes gathers around chromatin when DNA is damaged to assist with repair processes. The location of an enzyme also proved significant; for example, IMPDH2 helped maintain genome stability when located in the nucleus but influenced other pathways when confined to the cytoplasm.
These discoveries may affect how cancer treatments are developed since some drugs target metabolic activity while others focus on DNA repair mechanisms. If these systems are more interconnected than previously thought, this could explain why tumors with similar mutations sometimes respond differently to therapies.
"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," said Dr. Sdelci.
The authors note this is the first comprehensive evidence showing many metabolic enzymes reside within the nucleus. Mapping their locations and functions could eventually lead to new diagnostic biomarkers or vulnerabilities for anti-cancer drugs to exploit.
To advance this field further, researchers must determine what each enzyme does inside the nucleus—or if they are active at all. "Each enzyme may have its own unique nuclear function, so this must be addressed one by one," said Dr. Kourtis.
Another unresolved question concerns how large enzymes cross into the nucleus despite size restrictions imposed by nuclear pores—a mystery that could reveal new therapeutic targets if solved.
