Scientists from MIT have solved the mystery of why the forced switching on of genes responsible for DNA repair does not rejuvenate the retina in mice, but rather kills its cells. Their findings were presented in the journal Science Signaling.
Every day in any cell of our body there are 10-20 thousand small breakdowns in DNA, which lead to the rupture of its spirals. A whole complex of proteins and signaling molecules reacts to these breakdowns, which recognize them, assess the possibility of repair, connect broken threads, or signal the cell to self-destruct.
Russian and foreign scientists have been studying these systems for a long time, trying to understand exactly what types of DNA damage they repair, what affects their activity and whether it can be increased by making cells invulnerable to radiation and protecting their owner from cancer development.
Ten years ago, Samson said, her team conducted one of the first such studies. They monitored how the increased activity of the AAG gene, which is responsible for the elimination of small single lesions in one of the DNA strands, affects the functioning of the eyes of mice that received a "horse" dose of chemotherapy.
Scientists hoped that the enhanced work of the "immortality gene" would protect the retina of rodents from degeneration, but in reality exactly the opposite happened - the light-sensitive cells began to die even faster and the mice quickly became blind.
They spent the next ten years solving this riddle. The answer turned out to be very simple. It turned out that the AAG enzyme molecules cut out so many damaged DNA segments that this led to the inclusion of a special "death protein", a molecule of PARP that initiates necrosis, one of the variants of cellular suicide.
During normal DNA repair systems, this enzyme recognizes breaks in single strands of DNA, attaches to them and generates signals that cause other proteins to repair these damage. In the event that there are too many such breaks, the excessively high PARP activity deprives the cell of its reserves of "energy currency", ATP molecules, which leads to its decay and death.
The contents of the former cell, as Samson and her colleagues found out, enter the intercellular space and cause inflammation, attracting the attention of macrophages, special immune bodies that "digest" the remains of dead cells.
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They, in turn, produce a series of aggressive molecules that penetrate the still living receptors of the retina and further damage DNA. This leads to a new burst of AAG activity, activation of PARP, death of a new portion of cells, and increased inflammation. As a result, the entire tissue quickly self-destructs.
Similar processes, as subsequent experiments on mice showed, occur, albeit in a less dramatic form, in other tissues and organs of mice, including the cerebellum, bone marrow, and pancreas. In the near future, according to Samson, her team will study how these problems are characteristic of human tissues and individual cells.
