A new study has revealed over 200 metabolic enzymes attached directly to human DNA inside the cell nucleus, challenging traditional views of cellular processes. These enzymes form unique patterns in different tissues and cancers, described as a 'nuclear metabolic fingerprint.' The discovery suggests links between metabolism and gene regulation that may influence cancer development and treatment.
Scientists have identified more than 200 metabolic enzymes bound to chromatin, the packaging of DNA, within the human cell nucleus. This finding, published in Nature Communications on March 9, 2026, shows that enzymes typically associated with energy production in mitochondria are present in the nucleus across various cell types.
The research team, led by Dr. Sara Sdelci at the Centre for Genomic Regulation, used a technique to isolate proteins attached to chromatin. They analyzed 44 cancer cell lines and 10 healthy cell types from ten tissues. About 7 percent of chromatin-bound proteins were metabolic enzymes, indicating a potential 'mini metabolism' in the nucleus.
Patterns of these enzymes vary by tissue and cancer type. For instance, enzymes involved in oxidative phosphorylation, a key energy-generating process, were common in breast cancer cells but absent in lung cancer cells. This trend held in patient tumor samples, highlighting tissue-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, the study's first author.
Experiments revealed that certain enzymes, such as those for DNA synthesis and repair, cluster near damaged chromatin to aid genome repair. The enzyme IMPDH2, for example, supports genome stability when in the nucleus but affects different pathways in the cytoplasm.
"Many of these enzymes synthesize essential building blocks of life, and their nuclear localization is associated with DNA repair," noted Dr. Sdelci. "Their presence in the nucleus may therefore directly shape how cancer cells respond to genotoxic stress, a hallmark of many chemotherapeutic treatments."
The study raises questions about how large enzymes enter the nucleus despite size restrictions at nuclear pores, and whether all observed enzymes are active there. Researchers suggest this nuclear metabolism could explain varying cancer responses to therapies targeting metabolism or DNA repair, potentially informing future diagnostics and treatments.
