Researchers at the Center for Genomic Regulation (CRG) reveal that metabolic enzymes known for their role in energy production and nucleotide synthesis are taking on unexpected “second jobs” within the nucleus, orchestrating critical functions such as cell division and tissue repair. DNA.
The discovery, reported in two separate research papers published today in Nature Communicationsnot only challenges long-standing biological paradigms in cell biology, but also opens new avenues for anticancer therapies, particularly against aggressive tumors such as triple negative breast cancer (TNBC).
For decades, biology textbooks have clearly compartmentalized cellular functions. Mitochondria are the powerhouses of the cell, the cytoplasm is a bustling factory for protein synthesis, and the nucleus is the custodian of genetic information. However, Dr. Sara Sdelci and her CRG team have discovered that the boundaries between these cellular compartments are less defined than previously thought.
“Metabolic enzymes work outside their traditional neighborhood. It’s like finding out that the local baker is also a brewer in the next town. There’s an overlap in skill set, but they’re doing completely different jobs for completely different purposes,” says Dr. .Sdelci, lead author of both research articles.
“Surprisingly, its secondary functions in the nucleus are as critical as its primary metabolic functions. It is a new layer of complexity that we had not appreciated before,” he adds.
In one of the studies, researcher Dr. Natalia Pardo Lorente focused on the metabolic enzyme MTHFD2. Traditionally, MTHFD2 is located in the mitochondria, where it plays a key role in the synthesis of the building blocks of life and contributes to cell growth. Pardo Lorente’s work reveals that MTHFD2 also has a second job within the nucleus, where it plays a critical role in ensuring proper cell division.
The study is the first to demonstrate that the nucleus depends on metabolic pathways to maintain the integrity and stability of the human genome. “Our finding fundamentally alters our understanding of how cells are organized,” explains Dr. Pardo Lorente. “The nucleus is not just a passive storage space for DNA; it has its own needs and metabolic processes.”
In the second study, researchers Dr. Marta García-Cao and Dr. Lorena Espinar focused their attention on triple negative breast cancer, the most aggressive type of breast cancer that exists. The disease is responsible for approximately one in eight breast cancer diagnoses and accounts for approximately 200,000 new cases each year worldwide.
Typically, excessive DNA damage triggers cell death. However, TNBC has a propensity to accumulate DNA damage without consequences, making it resistant to conventional treatments. The study helps partly explain why: The metabolic enzyme IMPDH2 translocates to the nucleus of TNBC cells to assist in DNA repair processes. “IMPDH2 acts as a mechanic in the cell nucleus, controlling the DNA damage response that would otherwise kill the cancer cell,” explains García-Cao.
By experimentally manipulating IMPDH2 levels, the team found that they could tip the balance. The increase in IMPDH2 within the nucleus overwhelmed the cancer cells’ repair machinery, causing the cells to self-destruct. “It’s like overloading a sinking ship with more water: eventually, it sinks faster,” Espinar says. Their approach effectively forces TNBC cells to succumb to DNA damage to which they are normally resistant.
The study may also lead to new ways to control cancer. Research on IMPDH2 also studied its interaction with PARP1, a protein already targeted by existing anti-cancer drugs. “IMPDH2 could serve as a biomarker to predict which tumors will respond to PARP1 inhibitors,” explains García-Cao.
Both studies contribute to an emerging field of targeted cancer therapies by exploiting their metabolic vulnerabilities. “Metabolic enzymes are a completely new class of therapeutic targets that we can exploit. They pave the way for a two-pronged attack on cancer cells: disrupting their energy production while impairing their ability to repair DNA and divide properly. Combining this “Conventional treatments could give the cancer less room to adapt and help address common drug resistance mechanisms,” explains Dr. Sdelci.
While the concept of enzymes playing multiple roles within a cell is not entirely new, studies show that the scope and importance of these “second roles” are only beginning to be appreciated. “This is a paradigm shift and there may still be many more moonlighting metabolic enzymes to be discovered,” says Dr. Pardo Lorente. “The cell is more interconnected than we thought and that opens up interesting possibilities for science and medicine.”