Maintaining genome integrity via DNA damage repair is a key biological process required to suppress diseases, including growth retardation, malignancy, neurodegeneration, and congenital anomalies. Recent years have seen remarkable progress in unraveling the mechanisms of the DNA damage response, broadening our knowledge of the diverse DNA damage response pathways.
A systematic understanding of the metabolic requirements crucial for DNA damage repair has yet to be achieved. To overcome this difficulty, a research team led by Sara Sdelci at the Centre for Genomic Regulation (CRG) in Barcelona and Joanna Loizou at the CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Medical University of Vienna conducted numerous experiments to determine which metabolic enzymes and processes are crucial for a cell’s DNA damage response.
The researchers experimentally used the standard chemotherapeutic drug etoposide to cause DNA damage in human cell lines. Etoposide ruptures DNA strands and inhibits an enzyme that aids in damage repair. Unexpectedly, causing DNA damage caused reactive oxygen species to be produced and to build up inside the nucleus. The scientists discovered that cellular respiratory enzymes, a significant source of reactive oxygen species, moved from the mitochondria to the nucleus in reaction to DNA damage.
Dr. Sara Sdelci, a corresponding author of the study and Group Leader at the Centre for Genomic Regulation, said, “The findings represent a paradigm shift in cellular biology because it suggests the nucleus is metabolically active. Where there’s smoke, there’s fire, and where there are reactive oxygen species, there are metabolic enzymes at work. Historically, we’ve considered the nucleus a metabolically inert organelle that imports all its needs from the cytoplasm. Still, our study demonstrates that another type of metabolism exists in cells and is found in the nucleus.”
All of the metabolic genes critical for cell survival in this situation were found by the researchers using CRISPR-Cas9. These studies showed that cells direct the antioxidant enzyme PRDX1, typically found in mitochondria, to move to the nucleus and scavenge any reactive oxygen species to stop additional damage. Additionally, PRDX1 was discovered to heal the damage by controlling the cellular availability of aspartate, an essential raw material for the production of nucleotides, the DNA’s building blocks.
Dr. Sdelci said, “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 crisis, the nucleus responds by appropriating mitochondrial machinery and establishing an emergency rapid-industrialization policy.”
The results can direct future cancer research directions. Some anti-cancer medications, like the one used in this study, etoposide, destroy tumor cells by breaking their DNA and impeding the repair process. The cancer cell starts an autodestructive process if enough damage builds up.
The results may direct future cancer research directions. Some anti-cancer medications, like the one used in this study, etoposide, destroy tumor cells by breaking their DNA and impeding the repair process. The cancer cell starts an autodestructive process if enough damage builds up.
The study’s authors urge more research into novel approaches like dual therapy, which combines etoposide with medications that also increase the production of ROS to combat drug resistance and hasten the death of cancer cells. They also postulate that combining etoposide with inhibitors of nucleotide synthesis could enhance the drug’s effects by blocking DNA damage repair and guaranteeing that cancer cells properly self-destruct.
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 learned 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.”