Antioxidant enzymes come to the rescue of DNA damage

The nucleus has historically been considered metabolically inert, importing all of its needs through supply chains in the cytoplasm. Now, a new study led by researchers at the Center for Genomic Regulation (CRG) in Barcelona and CeMM/Medical University of Vienna has revealed that in a state of crisis, such as DNA damage, the nucleus protects itself by calling on antioxidant enzymes to save. The new results are published in Biology of molecular systems in an article titled A metabolic map of DNA damage response identifies PRDX1 in the control of nuclear scavenging of ROS and aspartate availability and may lead to future cancer research and clues to overcoming drug resistance.

‘While cellular metabolism affects the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved,’ the researchers wrote. “Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response.”

Cells balance their energy needs and avoid damaging DNA by containing metabolic activity outside the nucleus and inside the cytoplasm and mitochondria. Despite the central role of cellular metabolism in maintaining genome integrity, systematic and unbiased studies on how metabolic perturbations affect DNA damage and the repair process have not been conducted. This is especially important for diseases such as cancer, characterized by their ability to hijack metabolic processes for unlimited growth.

The researchers, led by Sara Sdelci, PhD, of the CRG in Barcelona and Joanna Loizou, PhD, of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Medical University of Vienna, conducted several experiments to identify which enzymes and metabolic processes are essential for a cell’s response to DNA damage.

The team experimentally induced DNA damage in human cell lines using a common chemotherapy drug known as etoposide. They observed that cellular respiratory enzymes relocated from mitochondria to the nucleus in response to DNA damage.

“Where there is smoke there is fire, and where there are reactive oxygen species there are metabolic enzymes at work. We have historically 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,” Sdelci explained.

The researchers also used CRISPR-Cas9 to identify all metabolic genes important for cell survival in this scenario. “Further analyzes identified that peroxiredoxin 1, PRDX1, contributes to DNA damage repair,” the researchers wrote. “During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Furthermore, loss of PRDX1 reduces the availability of aspartate, which is required for DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.

PRDX1 is like a pool cleaner robot. Cells have been known to use it to keep their insides clean and prevent the buildup 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 the mitochondrial machinery and establishes a policy of rapid industrialization of emergency, Sdelci said.

The study authors call for the exploration of new strategies such as dual treatment combining etoposide with drugs that also increase 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 enhance the drug’s effect by preventing DNA damage repair and ensuring that cancer cells self-destruct properly.

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