2023-06-02 10:27:31
A typical human cell is metabolically active, with a bustle of chemical reactions that convert nutrients into energy and useful products that sustain life. These reactions also create reactive oxygen species, dangerous byproducts such as hydrogen peroxide they 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 oxidation, reactive oxygen species threaten the integrity of a genome.
Cells are thought to delicately balance their energy needs and prevent DNA damage by containing metabolic activity outside the nucleus and within the cytoplasm and mitochondria.
Antioxidant enzymes are deployed to clean reactive oxygen species at their source before they reach DNA
Las antioxidant enzymes unfold for clean up reactive species of oxygen at their source before they reach the DNA, a defensive strategy that protects the approximately three billion nucleotides from undergoing potentially catastrophic mutations. If genetic damage occurs anyway, cells momentarily stop and carry out repairs, synthesizing new building blocks and filling in the gaps.
Despite the central role of cell metabolism in maintaining genome integrity, there have not been any systematic and unbiased studies on how metabolic perturbations affect DNA damage and the repair process. This is particularly important for diseases such as cancer, characterized by their ability to hijack metabolic processes and proliferate without restrictions.
Reactive oxygen species threaten the integrity of a genome
A research team led by Sara Sdelci of the Center for Genomic Regulation (CRG), in Barcelona, and Joanna Loizou at the Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences carried out several experiments to identify which enzymes and metabolic processes are essential for the DNA damage response of a cell. The findings have been published this Wednesday in the journal Molecular Systems Biology.
The researchers experimentally induced DNA damage in human cell lines using a chemotherapy drug common known as etoposide. It works by breaking DNA strands and blocking an enzyme that helps repair damage.
Surprisingly, the induction of DNA damage resulted in the generation of reactive oxygen species and accumulation 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,” says Sdelci, adding: “Historically, we have thought of the nucleus as a metabolically inert organelle that it imports all its needs from the cytoplasm, but our study shows that there is another type of metabolism in cells and it is found in the nucleus.”
Where there are reactive oxygen species there are metabolic enzymes at work
Sara Sdelci (CRG)
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 order to the enzyme PRDX1an 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 cell availability of aspartate, a raw material that is critical for the synthesis of nucleotides, the building blocks of DNA.
“PRDX1 is like a pool cleaner robot. Cells are known to use it to keep their interior ‘clean’ and prevent the buildup of reactive oxygen species, but never before at the nuclear level. This proves that, in a state of crisis, the nucleus responds by appropriating the mitochondrial machinery and establishes a policy of rapid emergency industrialization”, says Sdelci.
The findings may guide future lines of cancer research. Some anticancer drugs, such as the etoposide used in this study, kill tumor cells by damaging your DNA and inhibiting the repair process. If enough damage accumulates, the cancer cell begins a process in which it self-destructs.
Some drugs used in chemotherapy kill tumor cells by damaging their DNA
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, which means that even in the presence of oxygen they generate energy without producing 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 authors of the study call for the exploration of new strategiessuch as dual therapy combining etoposide with drugs that also increase reactive oxygen species generation to overcome drug resistance and kill cancer cells faster.
They also hypothesize that the combination of etoposide with inhibitors of nucleotide synthesis processes could potentiate the effect of the drug by preventing DNA damage repair and ensuring that cancer cells self-destruct properly.
Joanna Loizou highlights the value of adopting data-driven approaches to discover new biological processes. “Using unbiased technologies such as CRISPR-Cas9 detection and metabolomics, we have learned how the two fundamental cellular processes of dna repair and metabolism,” he says.
“Our findings shed light on how addressing these two pathways in cancer could improve therapeutic outcomes for patients,” concludes the researcher.
Reference:
Moretton et al. “A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability”, Molecular Systems Biology (2023)
Rights: Creative Commons.
#Antioxidant #enzymes #repair #DNA #damage
