An international team of scientists from Spain and Austria has determined that a mechanism is functioning inside the cell nucleus that allows it to avoid DNA damage due to the accumulation of reactive oxygen species. This explains why cancer cells become resistant to DNA-targeting chemotherapy drugs. This is reported in an article published in the journal Molecular Systems Biology.

Antioxidant enzymes are used by the cell to detoxify reactive oxygen species (ROS), which are a by-product of cellular respiration. It was believed that ROS interacted with various organic molecules, including DNA, causing their oxidation and destruction.

In the study, the scientists experimentally induced DNA damage in human cell lines using the chemotherapy anti-cancer drug etoposide. Etoposide breaks DNA strands and blocks an enzyme that helps repair damage.

It turned out that DNA damage led to the formation and accumulation of reactive oxygen species inside the cell nucleus. At the same time, respiratory enzymes, which are the main source of reactive oxygen species, moved from mitochondria to the nucleus in response to DNA damage. This finding suggests that the nucleus is metabolically active, although scientists have previously held the view that the nucleus is inert in this respect.

The researchers also used the CRISPR-Cas9 system to identify all genes important for cell survival. The antioxidant enzyme PRDX1, which is also normally present in mitochondria, travels to the nucleus and scavenges reactive oxygen species present to prevent further damage. PRDX1 repairs damage by regulating the availability of aspartate, which is critical for nucleotide synthesis. Thus, the cells become resistant to etoposide.