How Nuclear Metabolism Impacts Chromatin Function and Cancer Progression

Researchers at the Centre for Genomic Regulation have found that more than 200 metabolic enzymes—many normally associated with generating energy in mitochondria—are also found sitting directly on top of human DNA, reshaping how scientists think about nuclear metabolism. The work shows that different cell types, tissues, and cancers display unique patterns of metabolic enzymes compartmentalized inside the nucleus and interacting with chromatin, giving each cell what the authors describe as a “nuclear metabolic fingerprint.” This finding suggests that nuclear metabolism may help explain how tumors grow, adapt, or resist treatment.

The researchers used a method that isolates proteins physically attached to chromatin and applied it to 44 cancer cell lines and 10 healthy cell types from ten tissues. They found that 7% of all chromatin‑bound proteins were metabolic enzymes, indicating that the nucleus may host its own independent “mini metabolism.” Among the most surprising findings were components of oxidative phosphorylation—the process that generates most of the cell’s energy—appearing as regular residents in the nucleus. The absence, presence, and abundance of these enzymes varied by cancer type: oxidative phosphorylation enzymes were common in breast cancer cells but largely absent in lung cancer cells, a pattern mirrored in patient tumor samples.

“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,” explained Sara Sdelci, corresponding author of the study published in Nature Communications. The team carried out experiments to probe what some of the metabolic enzymes are doing. They studied a group of enzymes that provide building blocks for DNA synthesis and repair and found they gather around chromatin when DNA is damaged, helping repair the genome. The enzyme IMPDH2 also behaved differently depending on location: when confined to the nucleus, it helped maintain genome stability, whereas when confined to the cytoplasm it affected other pathways instead. 

“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,” first author Savvas Kourtis noted.

The discovery raises questions about how cancer treatments that target either metabolism or DNA repair actually work, and why tumors with the same mutations can respond very differently to chemotherapy, radiotherapy or targeted inhibitors. Mapping the location and function of nuclear metabolic enzymes could ultimately help identify new biomarkers and vulnerabilities that anti‑cancer drugs might exploit, but, as Kourtis notes, “Each enzyme may have its own, unique nuclear function, so this must be addressed one by one.”