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HomeScienceAntioxidant enzymes are studied to understand their role in repairing DNA damage.

Antioxidant enzymes are studied to understand their role in repairing DNA damage.


The image shows the location of DNA damage (in the nucleus of these four cells – in green) and the uniformity of PRDX1 (in red, same location). Credit: Sarah Sdelci/CRG

A typical human cell is metabolically active, and chemical reactions occur that convert nutrients into energy and useful life-sustaining products. These reactions also create reactive oxygen species, which are dangerous byproducts like hydrogen peroxide that destroy the building blocks of DNA in the same way oxygen and water corrode metal and form rust. Similar to how buildings collapse from the cumulative effect of rust, ROS threatens the integrity of the genome.

Cells are thought to precisely balance their energy needs and avoid DNA damage by containing metabolic activity outside the nucleus and into the cytoplasm and mitochondria. Antioxidant enzymes are deployed to eliminate reactive oxygen species from their source before they reach DNA, a defense strategy that protects the roughly 3 billion nucleotides from suffering potentially catastrophic mutations. If DNA damage occurs anyway, cells pause, make repairs, synthesize new building blocks, and fill in the gaps.

Despite the central role of cellular metabolism in maintaining genome integrity, there has been no systematic and unbiased study on how metabolic perturbations affect the DNA damage and repair process. This is particularly important for diseases such as cancer, which are characterized by their ability to hijack metabolic processes for unrestrained growth.

A research team led by Sarah Sedelsey at the Center for Genome Regulation (CRG) in Barcelona and Joanna Loiseau at the Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna and the Medical University of Vienna tackled this challenge by conducting various experiments to identify enzymes and metabolic processes essential for the cell’s DNA damage response. . The results were 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 down strands of DNA and blocking an enzyme that helps repair damage. Surprisingly, inducing DNA damage led to 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 into the nucleus in response to DNA damage.

The results represent a paradigm shift in cellular biology because they indicate 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 thought the nucleus was a metabolically inactive organelle that imported all its needs from the cytoplasm, but our study shows that there is another type of metabolism present in cells and found in the nucleus,” he says. Dr Sedelsey, corresponding author of the study and group leader at the Center for Genomic Regulation.

The researchers also used CRISPR-Cas9 to identify all the metabolic genes that were important for cell survival in this scenario. These experiments revealed that cells instruct PRDX1, an antioxidant enzyme also found naturally in mitochondria, to travel to the nucleus and search for existing reactive oxygen species to prevent further damage. PRDX1 has also been found to repair damage by regulating the cellular availability of aspartate, a necessary raw material for the synthesis of nucleotides, the building blocks of DNA.

“PRDX1 is like an automated swimming pool cleaner. Cells are known to use it to keep their interior ‘clean’ and prevent the build-up of reactive oxygen species, but never before at the nuclear level. This is evidence that in a crisis, the nucleus responds by customizing mitochondrial machinery And it sets an emergency policy for rapid industrialization,” says Dr Sdelsey.

The findings could guide future lines of cancer research. Some anticancer drugs, such as the etoposide used in this study, kill cancer cells by damaging their DNA and inhibiting the repair process. If enough damage has been accumulated, the cancer cell begins the process of self-destruction.

During their experiments, the researchers found that knocking out metabolic genes essential for cellular respiration — the process that generates energy from oxygen and nutrients — causes normal healthy cells to become resistant to etoposide. This finding is significant because many cancer cells are glycolytic, which means that even in the presence of oxygen they generate energy without doing cellular respiration. This means that etoposide and other chemotherapies with a similar mechanism are likely to have a 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 reactive oxygen species production to overcome drug resistance and kill cancer cells faster. They also hypothesize that the combination of etoposide and inhibitors of nucleotide synthesis can potentiate the drug’s effect by preventing DNA damage repair and ensuring that cancer cells properly self-destruct.

Dr. Loiseau, corresponding author and group leader at the Center for Molecular Medicine and Medical University of Vienna, highlights the value of taking data-driven approaches to uncover novel biological processes. “Using unbiased technologies such as the CRISPR-Cas9 assay and metabolomics, we have learned how the two essential cellular processes of DNA repair and metabolism are intertwined. Our results have shed light on how targeting these two pathways in cancer can improve therapeutic outcomes for patients.”

more information:
Metabolic map of the DNA damage response identifies PRDX1 in controlling nuclear ROS scavenging and aspartate availability. Molecular Systems Biology (2023). DOI: 10.15252/msb.202211267

Provided by the Center for Genomic Regulation

the quote: Study Examines How DNA Damage Is Repaired by Antioxidant Enzymes (2023, June 1) Retrieved June 1, 2023 from https://phys.org/news/2023-05-dna-antioxidant-enzymes.html

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