Studies headed by researchers at the Centre for Genomic Regulation (CRG) have found that metabolic enzymes known for their roles in energy production and nucleotide synthesis are taking on unexpected “second jobs” within the nucleus, orchestrating critical functions like cell division and DNA repair.
The discovery challenges longstanding biological paradigms in cellular biology but also opens new avenues for cancer therapies, particularly against aggressive tumors like triple-negative breast cancer (TNBC).
For decades, biology textbooks have neatly compartmentalized cellular functions. Mitochondria are the powerhouses of the cell, the cytoplasm can be thought of as a busy factory floor for protein synthesis, and the nucleus is considered a custodian of genetic information. However, Sara Sdelci, PhD, and her team at the CRG have discovered that the boundaries between these cellular compartments are less defined than previously thought.
“Metabolic enzymes are moonlighting outside of their traditional neighborhood,” said Sdelci. “It’s like discovering your local baker is also a brewer in the next town over. There’s an overlap in the skillset, but they’re doing entirely different jobs for entirely different purposes … It’s a new layer of complexity that we hadn’t appreciated before … Surprisingly, their secondary roles in the nucleus are just as critical as their primary metabolic functions.”
Sdelci is senior author of the team’s two papers, which are reported in Nature Communications. Lorena Espinar, PhD, and Marta Garcia-Cao, PhD, are first authors of the report titled, “Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity,” and Natalia Pardo-Lorente, PhD, is first author of the paper titled, “Nuclear localization of MTHFD2 is required for correct mitosis progression.”
Pardo-Lorente and colleagues focused on the metabolic enzyme MTHFD2. Traditionally, MTHFD2 is found in the mitochondria, where it plays a key role in synthesizing the building blocks of life and contributing to cell growth. The authors’ newly reported in vitro work revealed that MTHFD2 also moonlights within the nucleus, where it plays a pivotal role in ensuring proper cell division. “… we show that the nuclear localization of the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) ensures mitosis progression,” they wrote. “Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability including the methyltransferases KMT5A and DNMT3B.”
The team’s experiments showed that loss of MTHFD2 induced severe methylation defect and impeded the correct completion of mitosis. “MTHFD2 deficient cells display chromosome congression and segregation defects and accumulate chromosomal aberrations,” they wrote. “Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, whereas restricting MTHFD2 to the nucleus is sufficient to ensure correct mitotic progression.”
The study is the first to demonstrate that the nucleus relies on metabolic pathways to maintain the integrity and stability of the human genome. “Our discovery uncovers a nuclear role for MTHFD2, supporting the notion that translocation of metabolic enzymes to the nucleus is required to meet precise chromatin needs,” they concluded. Added Pardo-Lorente, “Our finding fundamentally alters our understanding of how cells are organized. The nucleus isn’t just a passive storage space for DNA; it has its own metabolic needs and processes.”
In the second study, researchers García-Cao and Espinar focused on triple-negative breast cancer, the most aggressive type of breast cancer. The disease is responsible for around one in eight breast cancer diagnoses and amounts to roughly 200,000 new cases each year worldwide.
Usually, excessive DNA damage triggers cell death. However, TNBC has a propensity to accumulate DNA damage without consequence, making it resilient to conventional treatments. The team’s study helps partly explain why, by demonstrating that the metabolic enzyme IMPDH2 relocates to the nucleus of TNBC cells to assist in DNA repair processes. “First, we identified that IMPDH2 is enriched on chromatin in TNBC cell lines, TNBC patient samples, and in advanced breast cancers, conditions typically characterized by high levels of DNA damage,” the researchers explained. Their studies then found that IMPDH2 acts “like a mechanic” in the cell’s nucleus, controlling the DNA damage response that would otherwise kill the cancer cell, commented García-Cao. “Our study identifies a non-canonical nuclear role for IMPDH2, acting as a convergence point of nuclear metabolism and DNA damage response,” the investigators noted.
Through their in vitro studies the team found that by experimentally manipulating IMPDH2 levels, they could tip the balance. Increasing IMPDH2 within the nucleus overwhelmed the cancer cells’ repair machinery, causing cells to self-destruct. “It’s like overloading a sinking ship with more water—eventually, it sinks faster,” said Espinar. The approach effectively forces TNBC cells to succumb to the very DNA damage to which they are typically resilient.
The research on IMPDH2 studied its interaction with PARP1, a protein already targeted by existing cancer drugs. “On chromatin, IMPDH2 interacts with and modulates PARP1 activity by controlling the nuclear availability of NAD+ to fine-tune the DNA damage response,” the team explained. “These results suggest that nuclear IMPDH2 can control cell fate during DNA damage by interacting with PARP1 and regulating its activation levels.”
The findings could point to new ways of monitoring cancer. “Given the relevance of PARP1 in the treatment of various pathologies, it is possible that the presence of nuclear IMPDH2 could be used as a biomarker to stratify patients who will respond better or worse to PARP1 inhibition.”
Both studies contribute to an emerging field of therapies targeting cancer by exploiting its metabolic vulnerabilities. “Metabolic enzymes are an entirely new class of therapeutic targets for us to exploit. It paves the way for a two-pronged attack against cancer cells: disrupting their energy production while simultaneously impairing their ability to repair DNA and divide properly,” added Sdelci. “Combining this strategy with conventional treatments could give cancer less room to adapt and help tackle the usual mechanisms of drug resistance.”
While the concept of enzymes having multiple roles within a cell is not entirely new, the studies show the extent and significance of these “second jobs” are only beginning to be appreciated. “This is a paradigm shift and there might be many more moonlighting metabolic enzymes yet to be found,” said Pardo-Lorente. “The cell is more interconnected than we thought, and that opens up exciting possibilities for science and medicine.”
