The Metabolically Active Nucleus: A Paradigm Shift and Implications for Cancer Research
The human cell is continuously involved in metabolic activities that generate reactive oxygen species (ROS). ROS are dangerous byproducts like hydrogen peroxide that can cause damage to the genetic material, including the 3 billion nucleotides that make up DNA. To protect these building blocks, cells are thought to balance their energy needs and protect against DNA damage by keeping metabolic activity outside the nucleus and within the mitochondria. Antioxidant enzymes are then deployed to remove ROS at their source before they reach DNA. This defensive strategy protects the genome from undergoing potentially catastrophic mutations.
Despite the critical role of cellular metabolism in maintaining genome integrity, few studies have explored how metabolic perturbations affect the DNA damage and repair process. This knowledge gap is especially crucial for diseases such as cancer, which can hijack metabolic processes to foster unrestricted growth. A research team led by Sara Sdelci at the Center for Genomic Regulation in Barcelona and Joanna Loizou at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Medical University of Vienna addressed this challenge.
The research team carried out several randomized control group experiments to identify which enzymes and metabolic processes are essential for a cell’s DNA damage response. The findings, published in Molecular Systems Biology, reveal a surprising conclusion. In a crisis scenario such as widespread DNA damage, the nucleus protects itself by hijacking the mitochondrial machinery to carry out urgent repairs that immediately threaten the integrity of the genome.
The study’s key findings are:
* The research experimentally induced DNA damage in human cell lines using a common chemotherapy drug known as etoposide. Etoposide works by breaking strands of DNA and blocking an enzyme that helps repair damage. The induction of DNA damage resulted in the generation and accumulation of reactive oxygen species within the nucleus.
* The researchers found that knocking out metabolic genes that were crucial for cellular respiration, the process that generates energy from oxygen and nutrients, made normal healthy cells resistant to etoposide.
* The researchers noted that etoposide and other chemotherapies that target a similar mechanism have limited effects in treating glycolytic tumors. This is significant because many cancer cells are glycolytic, meaning that they generate energy without performing cellular respiration, even in the presence of oxygen.
* The researchers also used CRISPR-Cas9 to identify all metabolic genes that were necessary for cell survival in such a scenario. These experiments revealed that cells command PRDX1, an antioxidant enzyme also normally found in mitochondria, to travel to the nucleus and remove any ROS present to prevent further damage. PRDX1 was also found to repair damage by regulating the cellular availability of aspartate, a raw material that is essential for synthesizing nucleotides, the building blocks of DNA.
The Implications of the Findings for Cancer Research
The new findings have significant implications for cancer research. Many cancer drugs, such as the etoposide used in this study, kill tumor cells by damaging their DNA and inhibiting the repair process. If enough damage accumulates, the cancer cell begins a process in which it self-destructs.
The researchers found that glycolytic tumors would not self-destruct adequately in response to such chemotherapy. But the study’s authors also called for exploring other strategies, such as dual therapy that combines etoposide with drugs that also boost the generation of reactive oxygen species to overcome drug resistance and kill cancer cells faster.
The researchers also hypothesized that combining etoposide with inhibitors of nucleotide synthesis processes could potentiate the drug’s effect by preventing further DNA damage repair and ensuring that cancer cells self-destruct appropriately.
The Paradigm Shift in Cell Biology
The researchers’ findings represent a significant paradigm shift in cell biology. They suggest that the nucleus is not a metabolically inert organelle that imports all its needs from the cytoplasm. Another type of metabolism exists in cells is found in the nucleus. “Where there are reactive oxygen species, there are metabolic enzymes at work,” says Dr. Sara Sdelci, the study’s corresponding author, and group leader at the Center for Genomic Regulation.
Historically, scientists have thought of the nucleus as a metabolic extraction conduit that solely imports its needs from the cytoplasm. However, it appears that in a crisis, the nucleus responds by hijacking the mitochondrial machinery and establishes an emergency policy of rapid industrialization. The researchers’ discoveries have far-reaching consequences and require us to rethink our assumptions about metabolic strategies that cells use to protect themselves in case of damage.
Conclusion
The study findings show that a metabolically active nucleus can impact cancer research significantly. The researchers found that glycolytic tumors are resistant to etoposide and similar therapies. As such, new strategies such as dual therapy may be necessary, and combining chemotherapy with metabolic inhibitors and antioxidant enhancers could lead to more optimal outcomes.
Moreover, the discovery that the nucleus is not metabolically inert is a paradigm shift in cell biology that impacts how researchers study and understand cell metabolism. The implications of these findings not only affect cancer research but also offer promise for treating other genetic diseases. This study underscores the importance of pursuing unbiased, data-driven research approaches to identify new biological processes that can significantly impact medical intervention strategies.
Summary:
A team of researchers from the Center for Genomic Regulation in Barcelona and the CeMM Research Center for Molecular Medicine carried out several experiments to explore how metabolic perturbations affect the DNA damage and repair process, a knowledge gap crucial for cancer research. Their findings demonstrate that in crisis scenarios like widespread DNA damage, the nucleus hijacks the mitochondrial machinery to carry out urgent repairs that threaten the integrity of the genome. While many cancer drugs kill tumor cells by inhibiting the repair process, glycolytic tumors are resistant to these drugs. The study’s authors suggest that combining chemotherapy with metabolic inhibitors and antioxidant enhancers could lead to more optimal outcomes. Their findings also represent a significant paradigm shift in cell biology and shed light on cell metabolism. Researchers must continue pursuing unbiased approaches to identify new biological processes that could impact medical intervention strategies.
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In crisis, the nucleus calls on antioxidant enzymes to the rescue. The metabolically active nucleus is a profound paradigm shift with implications for cancer research.
points summary
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The human nucleus is metabolically active, according to the findings of a new study in Molecular Systems Biology carried out by researchers from the CRG in Barcelona and CeMM/Vienna University of Medicine,
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In a state of crisis, such as widespread DNA damage, the nucleus protects itself by hijacking the mitochondrial machinery to carry out urgent repairs that threaten the integrity of the genome.
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The findings represent a paradigm shift because the nucleus has historically been considered to be metabolically inert, importing all of its needs through supply chains in the cytoplasm.
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Cancer hijacks cell metabolism for unrestricted growth. The findings may help guide future lines of cancer research by offering new clues for overcoming drug resistance and, ultimately, designing new treatments.
main text
A typical human cell is metabolically active, roaring with chemical reactions that convert nutrients into energy and useful life-sustaining products. These reactions also create reactive oxygen species, dangerous byproducts like hydrogen peroxide that damage the building blocks of DNA in the same way that oxygen and water corrode metal and form rust. Just as buildings collapse from the cumulative effect of rust, reactive oxygen species threaten the integrity of the genome.
Cells are thought to delicately balance their energy needs and avoid DNA damage by containing metabolic activity outside the nucleus and within the cytoplasm and mitochondria. Antioxidant enzymes are deployed to remove reactive oxygen species at their source before they reach DNA, a defensive strategy that protects the roughly 3 billion nucleotides from undergoing potentially catastrophic mutations. If DNA damage occurs anyway, cells stop momentarily and carry out repairs, synthesizing new building blocks and filling in the gaps.
Despite the central role of cellular metabolism in maintaining genome integrity, there has been no systematic and unbiased study of how metabolic perturbations affect the DNA damage and repair process. This is particularly important for diseases such as cancer, which is characterized by its ability to hijack metabolic processes for unrestricted growth.
A research team led by Sara Sdelci at the Center for Genomic Regulation (CRG) in Barcelona and Joanna Loizou at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Medical University of Vienna addressed this challenge by bringing carried out several experiments to identify which enzymes and metabolic processes are essential for a cell’s DNA damage response. The findings are published today in the journal Molecular Systems Biology.
The researchers experimentally induced DNA damage in human cell lines using a common chemotherapy drug known as etoposide. Etoposide works by breaking strands of DNA and blocking an enzyme that helps repair damage. Surprisingly, the induction of DNA damage resulted in the generation and accumulation of reactive oxygen species within the nucleus. The researchers observed that cellular respiratory enzymes, a major source of reactive oxygen species, moved from the mitochondria to the nucleus in response to DNA damage.
The findings represent a paradigm shift in cell biology because they suggest that the nucleus is metabolically active. “Where there is smoke, there is fire, and where there are reactive oxygen species, there are metabolic enzymes at work. Historically, we have thought of the nucleus as a metabolically inert organelle that imports all its needs from the cytoplasm, but our study shows that another type of metabolism it exists in cells and is found in the nucleus,” says Dr. Sara Sdelci, corresponding author of the study and group leader in the Center for Genomic Regulation.
The researchers also used CRISPR-Cas9 to identify all metabolic genes that were important for cell survival in this scenario. These experiments revealed that cells command PRDX1, an antioxidant enzyme also normally found in mitochondria, to travel to the nucleus and remove any reactive oxygen species present to prevent further damage. PRDX1 was also found to repair damage by regulating the cellular availability of aspartate, a raw material that is essential for synthesizing nucleotides, the building blocks of DNA.
“PRDX1 is like a robotic pool cleaner. Cells have been known to use it to keep their interiors ‘clean’ and prevent the buildup of reactive oxygen species, but never before at the nuclear level. This is evidence that, in a In crises, the nucleus responds by hijacking the mitochondrial machinery and establishes an emergency policy of rapid industrialization,” says Dr. Sdelci.
The findings may guide future lines of cancer research. Some cancer drugs, such as the etoposide used in this study, kill tumor cells by damaging their DNA and inhibiting the repair process. If enough damage accumulates, the cancer cell begins a process in which it self-destructs.
During their experiments, the researchers found that knocking out metabolic genes critical for cellular respiration, the process that generates energy from oxygen and nutrients, made normal healthy cells resistant to etoposide. The finding is important because many cancer cells are glycolytic, meaning that even in the presence of oxygen they generate energy without performing cellular respiration. This means that etoposide and other chemotherapies with a similar mechanism are likely to have limited effect in the treatment of glycolytic tumors.
The study authors call for exploring new strategies, such as dual therapy that combines etoposide with drugs that also boost the generation of reactive oxygen species to overcome drug resistance and kill cancer cells faster. They also hypothesize that combining etoposide with inhibitors of nucleotide synthesis processes could potentiate the drug’s effect by preventing DNA damage repair and ensuring that cancer cells self-destruct properly.
Dr. Joanna Loizou, corresponding author and group leader at the Center for Molecular Medicine and the Medical University of Vienna, highlights the value of adopting data-driven approaches to discover new biological processes. “Using unbiased technologies such as CRISPR-Cas9 screening and metabolomics, we have learned how the two fundamental cellular processes of DNA repair and metabolism are intertwined. Our findings shed light on how targeting these two pathways in cancer could improve therapeutic outcomes for patients.
https://www.sciencedaily.com/releases/2023/06/230601160139.htm
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