The nucleus has historically been considered to be metabolically inert, importing all its needs through supply chains in the cytoplasm. Now, a new study by researchers at the Centre 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 the rescue. The new findings are published in Molecular Systems Biology in an article titled, “A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability,” and may lead to future cancer research and clues to overcoming drug resistance.
“While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved,” wrote the researchers. “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 within the cytoplasm and mitochondria. Despite the central role of cellular metabolism in maintaining genome integrity, there has been no systematic, unbiased study on how metabolic perturbations affect the DNA damage and repair process. This is particularly important for diseases like cancer, characterized by their ability to hijack metabolic processes for unrestricted growth.
The researchers, led by Sara Sdelci, PhD, at CRG in Barcelona and Joanna Loizou, PhD, at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Medical University of Vienna, carried out various experiments to identify which metabolic enzymes and processes are essential for a cell’s DNA damage response.
The team experimentally induced DNA damage in human cell lines using a common chemotherapy medication known as etoposide. They observed that cellular respiratory enzymes relocated from the mitochondria to the nucleus in response to DNA damage.
“Where there’s smoke there’s fire, and where there are 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,” explained Sdelci.
The researchers also used CRISPR-Cas9 to identify all the metabolic genes that were important for cell survival in this scenario. “Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair,” wrote the researchers. “During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the 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 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-industrialization policy,” said Sdelci.
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 hypothesize 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.