The metabolic activity of a normal human cell is rife with chemical
processes that transform food into energy and valuable compounds that
support life. Reactive oxygen species, which are harmful byproducts like
hydrogen peroxide that harm DNA's building blocks in a similar manner to how
oxygen and water erode metal and cause rust, are also produced by these
reactions. Reactive oxygen species put a genome's integrity at danger, much
as how rust causes structures to crumble over time.
It is assumed that by limiting metabolic activity to the cytoplasm,
mitochondria, and regions outside the nucleus, cells can finely balance
their energy requirements and prevent DNA damage. Antioxidant enzymes are
used as a defense mechanism to mop up reactive oxygen species at their
source before they reach DNA. This prevents the approximately 3 billion
nucleotides from experiencing potentially disastrous alterations. Cells
briefly halt and perform repairs, synthesising new building blocks and
filling in the gaps, if DNA damage nonetheless occurs.
Despite the crucial function of cellular metabolism in preserving genome
integrity, the impact of metabolic disturbances on the DNA damage and repair
process has not been well investigated. This is crucial for illnesses like
cancer, which are known for their capacity to seize control of metabolic
systems and drive unchecked development.
This problem has been addressed by a team of researchers led by Sara Sdelci
at the Centre for Genomic Regulation (CRG) in Barcelona and Joanna Loizou at
the CeMM Research Center for Molecular Medicine of the Austrian Academy of
Sciences in Vienna and the Medical University of Vienna. They have conducted
a number of experiments to determine which metabolic enzymes and processes
are crucial for a cell's DNA damage response. The results were released in
the journal Molecular Systems Biology today.
The researchers used the standard chemotherapeutic drug etoposide to
experimentally cause DNA damage in human cell lines. Breaking DNA strands
and inhibiting an enzyme that aids in damage repair are how etoposide
functions. Unexpectedly, causing DNA damage caused reactive oxygen species
to be produced and to build up inside the nucleus. The scientists discovered
that in reaction to DNA damage, cellular respiratory enzymes, a significant
source of reactive oxygen species, moved from the mitochondria to the
nucleus.
The findings imply the nucleus is metabolically active, which represents a
paradigm change in cellular biology. "Fire starts where there is smoke, and
metabolic enzymes are active where there are reactive oxygen species. Our
study disproves the conventional wisdom that the nucleus is a metabolically
inert organelle that imports all of its requirements from the cytoplasm and
that another type of metabolism occurs in cells and is located in the
nucleus, according to Dr. Sdelci, the study's corresponding author and Group
Leader at the Centre for Genomic Regulation.
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, which is typically located in
mitochondria, to go to the nucleus and scavenge any reactive oxygen species
there in order to stop additional damage. Additionally, PRDX1 was discovered
to reverse the damage by controlling the cellular availability of aspartate,
a necessary raw material for the synthesis of nucleotides, the DNA's
building blocks.
"PRDX1 is similar to an automated pool cleaning. It has never been used at
the nuclear level, despite the fact that cells are known to employ it to
maintain their interiors "clean" and avoid the buildup of reactive oxygen
species. This demonstrates how the nucleus adopts mitochondrial machinery in
times of stress and implements an emergency quick industrialization program,
claims Dr. Sdelci.
The results can direct future cancer research directions. Some anti-cancer
medications, like the experimental drug etoposide, kill tumor cells by
disrupting their DNA and impeding the process of repair. The cancer cell
starts an autodestructive process if enough damage builds up.
In their tests, the scientists discovered that normal, healthy cells were
resistant to etoposide when metabolic genes crucial for cellular
respiration—the mechanism that converts oxygen and nutrients into
energy—were knocked off. The discovery is significant since many cancer
cells are glycolytic, which means that they produce energy even in the
presence of oxygen without engaging in cellular respiration. As a result, it
is anticipated that etoposide and other chemotherapy drugs with a comparable
mechanism will only have a modest impact on the treatment of glycolytic
cancers.
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, in order to combat drug resistance and hasten the death
of cancer cells. Additionally, they propose that combining etoposide with
inhibitors of nucleotide synthesis might increase the drug's effectiveness
by blocking DNA damage repair and guaranteeing that cancer cells properly
self-destruct.
Dr. Loizou, the group leader at the Centre for Molecular Medicine and the
Medical University of Vienna and the corresponding author, emphasizes the
need of using data-driven methods to identify novel biological processes.
"We have discovered how the two essential biological processes of DNA repair
and metabolism are connected by employing unbiased technologies such as
CRISPR-Cas9 screening and metabolomics. Our research clarifies how focusing
on these two cancer-related pathways might help patients receive more
effective treatment.
