Researchers have uncovered that metabolic enzymes, typically recognized for their functions in energy production and nucleotide synthesis, are also taking on unexpected roles within the nucleus, managing essential processes such as cell division and DNA repair. This finding not only challenges long-held beliefs in cellular biology but also suggests new strategies for cancer treatment, particularly against aggressive cancers like triple-negative breast cancer (TNBC).
Researchers at the Centre for Genomic Regulation (CRG) have found that metabolic enzymes, known for their energy production and nucleotide synthesis roles, are unexpectedly taking on additional responsibilities within the nucleus, managing essential activities like cell division and DNA repair.
This discovery, detailed in two new research papers published in Nature Communications, not only disputes traditional views in cellular biology but also opens up potential new treatments for cancer, especially for challenging cancers like triple-negative breast cancer (TNBC).
For many years, biology textbooks neatly categorized cellular activities. Mitochondria were labeled as the cell’s energy producers, the cytoplasm was seen as a busy site of protein creation, and the nucleus was thought of as a mere holder of genetic material. Nevertheless, Dr. Sara Sdelci and her colleagues at CRG have found that the distinct roles of these cellular areas are not as clear-cut as once believed.
“Metabolic enzymes are functioning in ways we didn’t expect, like discovering your neighborhood baker also runs a brewery in another town. While they share some skills, they’re handling very different tasks,” says Dr. Sdelci, the lead author on both studies.
“Interestingly, their roles in the nucleus are just as vital as their main metabolic responsibilities. This adds a layer of complexity we hadn’t recognized before,” she notes.
In one study, researcher Dr. Natalia Pardo Lorente explored the enzyme MTHFD2, usually found in mitochondria where it assists in creating essential building blocks for life and promotes cell growth. Her investigation shows that MTHFD2 also works within the nucleus, playing a crucial role in facilitating correct cell division.
This research is the first to show that the nucleus depends on metabolic pathways to uphold the stability and integrity of the human genome. “Our results fundamentally change how we view cell organization,” Dr. Pardo Lorente explains. “The nucleus isn’t merely a passive DNA storage area; it possesses its own metabolic requirements and functions.”
In the second study, researchers Dr. Marta GarcÃa-Cao and Dr. Lorena Espinar examined triple-negative breast cancer, recognized as the most aggressive form of breast cancer. This type accounts for around one in eight breast cancer diagnoses and leads to roughly 200,000 new cases globally each year.
Typically, significant DNA damage leads to cell death. However, TNBC can accumulate DNA damage without negative consequences, making it resistant to standard treatments. This study sheds some light on the reason: the enzyme IMPDH2 moves to the nucleus of TNBC cells to support DNA repair processes. “IMPDH2 acts like a mechanic in the cell’s nucleus, managing the DNA damage response that would otherwise lead to cell death,” Dr. GarcÃa-Cao explains.
By experimentally adjusting IMPDH2 levels, the team was able to tip the scale. Enhancing IMPDH2 in the nucleus overloaded the cancer cells’ repair mechanisms, causing the cells to self-destruct. “It’s like sinking a ship by flooding it with more water – it eventually sinks faster,” says Dr. Espinar. This method forces TNBC cells to collapse under DNA damage that they would usually withstand.
The study may also pave the way for new cancer monitoring techniques. Their research on IMPDH2 examined its interaction with PARP1, a protein currently targeted by various cancer therapies. “IMPDH2 could be a useful biomarker for predicting which tumors will respond to PARP1 inhibitors,” Dr. GarcÃa-Cao explains.
Both studies contribute to a growing area of therapies that target cancer by taking advantage of its metabolic weaknesses. “Metabolic enzymes represent a novel class of therapeutic targets for exploration. This could allow for a dual approach against cancer cells: disrupting their energy supplies while simultaneously hindering their DNA repair and division processes. Merging this strategy with existing treatments could reduce cancer’s adaptability and help overcome common resistance mechanisms,” Dr. Sdelci elaborates.
While the idea of enzymes serving multiple roles in a cell isn’t completely new, these studies highlight the importance and extent of these “second jobs” that are just starting to gain recognition. “This represents a significant shift in understanding, and we might find many more multifunctional metabolic enzymes in the future,” Dr. Pardo Lorente concludes. “The interconnectivity of cellular functions is more intricate than we believed, leading to exciting prospects for both science and medicine.”
