Antioxidant Enzymes Repair DNA Damage
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“Where there’s smoke there’s fire, and where there’s reactive oxygen species there are metabolic enzymes at work. Historically, we’ve thought of the nucleus as a metabolically inert organelle that imports all its needs from the cytoplasm, but our study demonstrates that another type of metabolism exists in cells and is found in the nucleus,” says Dr. Sara Sdelci, corresponding author of the study and Group Leader at the Centre 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 order the enzyme PRDX1, an antioxidant enzyme also normally found in mitochondria, to travel to the nucleus and scavenge reactive oxygen species present to prevent further damage. PRDX1 was also found to repair the damage by regulating the cellular availability of aspartate, a raw material that is critical for synthesising nucleotides, the building blocks of DNA.
“PRDX1 is like a robotic pool cleaner. Cells are known to use it to keep their insides ‘clean’ and prevent the accumulation of reactive oxygen species, but never before at the nuclear level. This is evidence that, in a state of crisis, the nucleus responds by appropriating mitochondrial machinery and establishes an emergency rapid-industrialisation policy,” says Dr. Sdelci.
The findings can guide future lines of cancer research. Some anti-cancer drugs, such as etoposide used in this study, kill tumour cells by damaging their DNA and inhibiting the repair process. If enough damage accumulates, the cancer cell initiates a process where it autodestructs.
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 become 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 doing cellular respiration. This means etoposide, and other chemotherapies with a similar mechanism, is likely to have a limited effect in treating glycolytic tumours.
The authors of the study call for the exploration of new strategies such as dual treatment combining etoposide with drugs that also boost the generation of reactive oxygen species to overcome drug resistance and kill cancer cells faster. They also hypothesise that combining etoposide with inhibitors of nucleotide synthesis processes could potentiate the effect of the drug by preventing the repair of DNA damage and ensuring cancer cells self-destruct correctly.
Dr. Joanna Loizou, corresponding author and Group Leader at the Centre for Molecular Medicine and the Medical University of Vienna, highlights the value of taking data-driven approaches to uncover new biological processes. ‘By using unbiased technologies such as CRISPR-Cas9 screening and metabolomics, we have learnt about 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 might improve therapeutic outcomes for patients’.
Reference: Moretton A, Kourtis S, Gañez Zapater A, et al. A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability. Mol Syst Biol. 2023;n/a(n/a):e11267. doi: 10.15252/msb.202211267
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