In Paradigm Shift, Study Shows Antioxidant Enzymes Repair DNA Damage

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The image illustrates the location of DNA damage (in the nucleus of these four cells green) and the colocalization of PRDX1 (in red, same place). Credit: Sara Sdelci/CRG

Key points:

  • For the first time, researchers have shown the human nucleus is metabolically active.
  • In a state of crisis, such as widespread DNA damage, the nucleus protects itself by appropriating mitochondrial machinery to carry out urgent repairs.
  • The findings can help guide future lines of cancer research by offering new clues to overcome drug resistance.

Cells are thought to delicately balance their energy needs and avoid damaging DNA by containing metabolic activity outside the nucleus and within the cytoplasm and mitochondria. Antioxidant enzymes are deployed to mop up reactive oxygen species at their source before they reach DNA, a defensive strategy that protects the roughly 3 billion nucleotides from suffering potentially catastrophic mutations. If DNA damage occurs anyway, cells pause 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 is little research on how metabolic perturbations affect the DNA damage and repair process. In a study published in Molecular Systems Biology, an international research team from Barcelona and Austria addressed that oversight.

The team experimentally induced DNA damage in human cell lines using a common chemotherapy medication known as etoposide. Etoposide works by breaking DNA strands and blocking an enzyme which helps repair the damage. Surprisingly, inducing DNA damage resulted in reactive oxygen species being generated and accumulating inside the nucleus.The researchers observed that cellular respiratory enzymes, a major source of reactive oxygen species, relocated from the mitochondria to the nucleus in response to DNA damage.  

These findings represent a paradigm shift in cellular biology because it suggests the nucleus is metabolically active.

In their study, 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 synthesizing nucleotides, the building blocks of DNA. 

The team says their recent findings can guide future lines of cancer research. For example, some anti-cancer drugs—such as etoposide used in this study—kill tumor cells by damaging their DNA and inhibiting the repair process. If enough damage accumulates, the cancer cell initiates a process where it autodestructs.

 

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