Cover story: The (outer) guardian of the genome

The genetic code for protein p53 may be the most important factor
in protecting human cells from cancer caused by DNA-damaging agents.
This protein allows cells to repair DNA damage to prevent cancer, which is why it is nicknamed the "guardian of the genome.
"
Inactivation
of p53 can be found in about half of tumors.
Cells lacking p53 function become genomically unstable, meaning they are prone to acquire mutations in DNA that help tumors grow in uncontrolled ways, form metastases, and resist treatment
.
As a result, cancer cells become more aggressive
.

But maintaining the stability of a cell's genome (DNA) even without a surrounding DNA disruptor is an extremely difficult task
.
The researchers suspect that p53's protective function also covers healthy cells
.
However, the mechanism by which this protein acquires this ability is unclear
.
A research team led by Ivano Amelio, professor of systems toxicology at the University of Constance, and his colleague Marcel Leist, professor of in vitro toxicology and biomedicine at the University of Constance, now have a new understanding
of the mystery.

Cells and their DNA integrity are especially dangerous when dividing, because they copy their own DNA
in the process.
"Just like other copying processes, such as copying files or copying digital files, if the template is moved or changed during the copying process, the consequences can be catastrophic
.
So when DNA is copied, genes can't be transcribed — i.
e.
used as templates for proteins," Amelio explains
.
If they are transcribed anyway, severe disruption can occur, leading to cancer-causing mutations
.
The findings of Amelio and his team suggest that p53 inactivation favors this replication-related damage
.
They found that p53 normally works by altering the way cells metabolize, preventing the activation of otherwise inactive regions of the
genome.

Scientists painstakingly dissect the underlying mechanisms down to the last detail
.
They used the knowledge that parts of the
genome called heterochromatin are densely arranged to block the transcription of genes in these regions.
Therefore, these regions are called "silent" regions, and they are controlled by so-called epigenetic mechanisms, that is, processes that do not affect the genes themselves, but their overall packaging and accessibility in the genome
.
One of the most interesting findings of this recent study is that, in the absence of p53, these normally inaccessible or "silent" regions of our DNA are transcribed, with catastrophic consequences
.

"Normally, transcription of these genomic regions should be tightly controlled, and p53, by controlling metabolism to make heterochromatin inaccessible, is key
to locking up their information," Amelio said.
When p53 is lost, such as in a tumor with p53 inactivation, the cell loses metabolic homeostasis and the information hidden in heterochromatin becomes unusually accessible and transcribed
.
This causes so much damage that it will drive cells into a genomic state of instability that facilitates and worsens cancer progression
.
"By unraveling this mechanism, we can demonstrate a link
between metabolism, epigenetic integrity, and genomic stability.
" In addition, we provide evidence that p53 represents a switch that controls the switch
of this protection system in response to environmental stress.
Amelio summed up the findings
.

The question of how p53-inactivated tumors develop genomic instability has puzzled the scientific community for quite some time
.
"Now we have determined that in these tumors, there is a problem at the metabolic level, reflected in the
integrity of the epigenome.
" Therefore, p53 should actually be called the guardian of the (epi-) genome
.
This important insight could guide research to identify potential new treatment strategies
for very common cancers carrying p53 inactivation.
Amelio concluded
.