Scientists have found that a cell’s nucleus is metabolically involved, wherein cellular enzymes mobilize to maintain DNA integrity after harm. This shift in our comprehension of cellular metabolism can contribute to the development of novel cancer therapies, considering that cancer cells frequently exploit metabolic mechanisms for their expansion.
In times of crisis, the nucleus beckons antioxidant enzymes for assistance. This notion of a metabolically active nucleus represents a substantial conceptual shift with ramifications for cancer research.
According to a new study in Molecular Systems Biology by researchers at Barcelona’s CRG and Vienna’s CeMM/Medical University, the human nucleus is metabolically active. In a crisis scenario, like extensive DNA damage, the nucleus safeguards itself by harnessing mitochondrial machinery to execute critical repairs that jeopardize the integrity of the genome. The discovery implies a significant change in understanding, as historically, the nucleus was thought to be metabolically dormant, receiving all necessary resources through cytoplasmic channels.
Cancer takes over cellular metabolism to facilitate uncontrolled growth. The new findings could assist in directing future cancer research by providing insights to surmount drug resistance and design new therapies.
The provided image shows DNA damage (in green, within the nucleus of these four cells) and the colocalization of PRDX1 (in red, at the same location). Credit: Sara Sdelci / CRG
A typical human cell is metabolically vibrant, abuzz with chemical reactions converting nutrients into energy and valuable products essential for life. However, these reactions produce reactive oxygen species, harmful by-products such as hydrogen peroxide, which harm DNA’s building blocks much like oxygen and water corrode metal to form rust. Just as structures crumble from the cumulative impact of rust, reactive oxygen species pose a risk to the integrity of a genome.
It’s commonly believed that cells skillfully balance their energy needs while avoiding DNA damage by confining metabolic activity to the cytoplasm and mitochondria, and away from the nucleus. To guard against these potentially catastrophic mutations, antioxidant enzymes are dispatched to neutralize reactive oxygen species before they reach the DNA, providing protection to the nearly 3 billion nucleotides. If DNA damage occurs, cells briefly halt and perform repairs, creating new building blocks and patching up the gaps.
Despite the key role of cellular metabolism in preserving the integrity of the genome, there hasn’t been a comprehensive, unbiased study on how metabolic disturbances impact the DNA damage and repair processes. This is especially relevant in diseases like cancer, marked by their ability to seize metabolic processes for unchecked growth.
A photograph of the group led by Dr. Sara Sdelci at the Centre for Genomic Regulation, in Barcelona. Credit: CRG
Led by Sara Sdelci at Barcelona’s Centre for Genomic Regulation (CRG) and Joanna Loizou at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna, a research team set out to identify metabolic enzymes and processes essential for a cell’s DNA damage response. The results are published in the Molecular Systems Biology journal.
The team induced DNA damage experimentally in human cell lines using etoposide, a common chemotherapy drug. It works by breaking DNA strands and blocking an enzyme that aids in repairing the damage. Strikingly, the induction of DNA damage led to the accumulation of reactive oxygen species within the nucleus. Cellular respiratory enzymes, a significant source of reactive oxygen species, were seen to migrate from the mitochondria to the nucleus in response to DNA damage.
The findings suggest a substantial shift in cellular biology as they indicate metabolic activity within the nucleus. “Where there’s reactive oxygen species, there are metabolic enzymes at play. Traditionally, we viewed the nucleus as a metabolically inactive organelle importing its necessities from the cytoplasm. However, our study reveals an alternative type of metabolism within cells, occurring in the nucleus,” states Dr. Sara Sdelci, the study’s corresponding author and Group Leader at the Centre for Genomic Regulation.
By employing CRISPR-Cas9, the researchers identified all metabolic genes crucial for cell survival under these conditions. The results unveiled that cells command the enzyme PRDX1, a typically mitochondrial antioxidant enzyme, to traverse to the nucleus and neutralize any reactive oxygen species present, preventing further damage. PRDX1 was also found to repair the damage by controlling the cellular availability of aspartate, a raw material vital for producing nucleotides, the building blocks of DNA.
Dr. Sdelci likens PRDX1 to a robotic pool cleaner, known for maintaining cellular cleanliness by preventing the accumulation of reactive oxygen species, but never before seen at the nuclear level. “This indicates that, in a crisis state, the nucleus responds by commandeering mitochondrial machinery and sets up an emergency rapid-industrialization policy,” says Dr. Sdelci.
The findings can direct future lines of cancer research. Some anti-cancer drugs, like the etoposide used in this study, kill tumor cells by damaging their DNA and inhibiting the repair process. If the damage accrues sufficiently, the cancer cell triggers a self-destruct process.
During their experiments, the researchers found that disabling metabolic genes vital for cellular respiration – the process of generating energy from oxygen and nutrients – rendered normal healthy cells resistant to etoposide. This is crucial because many cancer cells are glycolytic, meaning they generate energy without doing cellular respiration even in the presence of oxygen. This suggests that etoposide and chemotherapies with a similar mechanism are likely to have a limited effect in treating glycolytic tumors.
The study’s authors suggest exploring new strategies like dual treatment combining etoposide with drugs that also amplify the production of reactive oxygen species to overcome drug resistance and expedite the killing of cancer cells. They also theorize that combining etoposide with inhibitors of nucleotide synthesis processes could enhance the drug’s effect by preventing DNA damage repair and ensuring correct self-destruction of cancer cells.
Dr. Joanna Loizou, the corresponding author and Group Leader at the Center for Molecular Medicine and the Medical University of Vienna, emphasizes the benefits of data-driven approaches to reveal new biological processes. “By using unbiased technologies such as CRISPR-Cas9 screening and metabolomics, we’ve gained insights into how the two fundamental cellular processes of DNA repair and metabolism are interrelated. Our findings shed light on how targeting these two pathways in cancer might improve therapeutic outcomes for patients.”
Reference: “A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability” by Amandine Moretton, Savvas Kourtis, Antoni Gañez Zapater, Chiara Calabrò, Maria Lorena Espinar Calvo, Frédéric Fontaine, Evangelia Darai, Etna Abad Cortel, Samuel Block, Laura Pascual-Reguant, Natalia Pardo-Lorente, Ritobrata Ghose, Matthew G Vander Heiden, Ana Janic, André C Müller, Joanna I Loizou and Sara Sdelci, 1 June 2023, Molecular Systems Biology.
DOI: 10.15252/msb.202211267
Table of Contents
Frequently Asked Questions (FAQs) about Cellular Metabolism in DNA Repair
What is the significance of the discovery regarding the metabolic activity of the cell nucleus?
The discovery of the metabolic activity of the cell nucleus is significant because it challenges the traditional notion of the nucleus being metabolically inert. It opens up new avenues for understanding cellular metabolism and its role in DNA repair, particularly in the context of diseases like cancer.
How do antioxidant enzymes contribute to DNA damage repair?
Antioxidant enzymes play a crucial role in DNA damage repair by neutralizing reactive oxygen species (ROS) that can harm DNA. These enzymes, such as PRDX1, scavenge ROS and prevent further damage. Additionally, PRDX1 regulates the availability of aspartate, a raw material required for synthesizing nucleotides, which are the building blocks of DNA.
What implications does this research have for cancer treatment?
This research has important implications for cancer treatment. Cancer cells often exploit metabolic processes for uncontrolled growth. Understanding the metabolic activity of the cell nucleus and the involvement of antioxidant enzymes in DNA repair can help develop strategies to overcome drug resistance and design more effective treatments targeting cancer cells’ unique metabolic characteristics.
How might the findings guide future lines of cancer research?
The findings can guide future lines of cancer research in several ways. They offer insights into potential drug combinations, such as combining DNA-damaging agents like etoposide with substances that enhance reactive oxygen species generation. Additionally, targeting nucleotide synthesis processes alongside DNA repair pathways could improve therapeutic outcomes by preventing DNA damage repair and promoting cancer cell self-destruction.
More about Cellular Metabolism in DNA Repair
- Molecular Systems Biology: Link to the study
- Centre for Genomic Regulation (CRG): CRG website
- CeMM Research Center for Molecular Medicine: CeMM website
- Medical University of Vienna: Medical University of Vienna website
