Metabolic enzymes play unexpected roles in cell division and DNA repair

Researchers at the Center for Genome Regulation (CRG) have discovered that metabolic enzymes, known for their roles in energy production and nucleotide synthesis, have taken on an unexpected “second job” in the nucleus, contributing to important tasks such as cell division and DNA repair. It was revealed that the function was being adjusted.

The findings were reported across two separate research papers published today. nature communicationsnot only challenges long-standing biological paradigms in cell biology, but also opens new avenues for cancer treatment, especially for malignancies such as triple-negative breast cancer (TNBC).

For decades, biology textbooks have neatly divided cell functions. Mitochondria are the powerhouses of the cell, the cytoplasm is the bustling factory floor for protein synthesis, and the nucleus is the custodian of genetic information. However, Dr. Sara Sdelci and her team at CRG discovered that the boundaries between these cellular compartments are not as clear-cut as previously thought.

Metabolic enzymes are attracting attention beyond traditional areas. It's like discovering your local bakery is also the neighboring town's brewery. Although there is overlap in skill sets, they are doing completely different jobs for completely different purposes. ”

Dr. Sara Sdelci, lead author of both research papers

“Surprisingly, their secondary role in the nucleus is just as important as their primary metabolic function. This is a new layer of complexity that we were not aware of before.” she added.

In one of the studies, researcher Dr. Natalia Pardo Lorente focused on the metabolic enzyme MTHFD2. Traditionally, MTHFD2 resides in mitochondria, where it plays an important role in synthesizing the building blocks of life and contributing to cell growth. Pardo Lorente's research revealed that MTHFD2 is also active in the nucleus, where it plays a pivotal role in ensuring proper cell division.

This 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 fundamentally changes our understanding of how cells are organized,” explains Dr. Pardo Lorente. “The nucleus is more than just a passive storage space for DNA. It has its own metabolic needs and processes.”

In the second study, researchers Dr. Marta Garcia-Cao and Dr. Lorena Espinar focused on triple-negative breast cancer, the most aggressive type of breast cancer. The disease is responsible for approximately 1 in 8 breast cancer diagnoses and causes approximately 200,000 new cases worldwide each year.

Excessive DNA damage usually causes cell death. However, TNBC tends to accumulate DNA damage without consequences and is resistant to conventional treatments. This study helps explain, in part, why the metabolic enzyme IMPDH2 relocates to the nucleus of TNBC cells to aid in DNA repair processes. “IMPDH2 acts like a mechanism in the cell's nucleus, controlling the DNA damage response that kills cancer cells,” explains Professor Garcia-Cao.

The researchers found that by ly manipulating IMPDH2 levels, they could disrupt the balance. When IMPDH2 increases in the nucleus, cancer cells' repair mechanisms become overactive, leading to cell self-destruction. “It's like adding too much water to a sinking ship, which ends up sinking faster,” Espinal said. Their approach effectively forces TNBC cells to succumb to the very DNA damage they normally tolerate.

This research could also lead to new ways to monitor cancer. Research on IMPDH2 also investigated its interaction with PARP1, a protein that is targeted by existing anticancer drugs. “IMPDH2 is biomarker “To predict which tumors will respond to PARP1 inhibitors,” Garcia-Cao explains.

Both studies contribute to new areas of cancer-targeted therapy by exploiting metabolic vulnerabilities. “Metabolic enzymes are a completely new class of therapeutic targets available to us. This opens the way to a two-pronged attack on cancer cells: by simultaneously interfering with cancer cells' energy production; It impairs the ability of DNA to repair and divide properly. This strategy and conventional treatments leave no room for cancer to adapt and may help address normal drug resistance mechanisms. Yes,” explains Dr. Sudersi.

Although the concept of enzymes with multiple roles within cells is not entirely new, research shows that the scope and importance of these “second jobs” is only beginning to be recognized. “This is a paradigm shift, and we may not yet have found metabolic enzymes like moonlight,” says Dr. Pardo Lorente. “Cells are more interconnected than we realize, which opens up exciting possibilities for science and medicine.”