Extracellular DNA: A Story in five questions
What can DNA do, besides transmitting information, how does it work outside the cell and can we use it
Polina Loseva, "The Attic"
Drawings: Alice Muravyeva
DNA is a key molecule that carries genetic information about the body's proteins. In cells, it is found in the nucleus and mitochondria (except for bacteria, which do not have nuclei and mitochondria). The cell is able to read this information, that is, synthesize the proteins encoded in it, and pass it on to daughter cells. However, DNA can be detected not only inside cells, but also outside – such molecules are called extracellular DNA (vcDNA). They exist in tissues by themselves and affect the functioning of surrounding cells.
How is it that DNA is outside the cell?
Bacterial cells can release DNA into the environment – this is due to the processes of their reproduction and information exchange. For example, antibiotic resistance is spreading: one bacterium acquires the corresponding gene, copies and shares it with the rest of the population. In eukaryotic (nuclear) organisms, such processes have been unknown for a long time: it was believed that they use DNA only for storing, reading and transmitting information.
But in 1948, extracellular DNA was found in blood plasma – a fraction of DNA that is not related to cells and exists separately from them. Over the following years, scientists have found such DNA in all studied organisms, from plants to animals and humans. It was found in the intercellular substance, in circulating fluids and even in individual cell cultures. It seems that DNA outside cells occurs regularly and, therefore, may play a role in the life of the organism.
Extracellular DNA is not like normal DNA. Genomic DNA consists of long strands-chromosomes, and vkDNA is a set of small sequences, sometimes a million times shorter than a chromosome. Whether the choice of these sequences is accidental or not is still a controversial issue.
Extracellular DNA is not always in solution by itself. Sometimes it is associated with histones – proteins that the cell uses for compact packaging of DNA strands in the nucleus. In other cases, vcDNA can occur inside exosomes – vesicles surrounded by a membrane that bud off from cells, travel through the body and can merge with other cells. Moreover, one group of scientists isolated from the blood of animals a whole complex of DNA, fats and proteins responsible for copying it. That is, probably, whole molecular machines are floating around the body, copying and distributing information right on the go. However, it is not yet known how much of the total vcDNA is made up of such structures.
Where does extracellular DNA come from?
It seems logical that the vcDNA is not formed by itself, but is secreted by cells. What can make cells throw out molecules carrying their hereditary information?
The cell death hypothesis suggests that DNA is released when cells are destroyed. This theory helps explain why vcDNA is represented by small fragments: for example, in apoptosis (programmed cell death) The DNA inside the cell is cut into small sections before the whole cell disintegrates. It is also consistent with the fact that in conditions accompanied by cell death (myocardial infarction, burns), the amount of vcDNA in the blood increases.
But not everything is so simple: extracellular DNA was found in any tissue cultures, even where there was no mass cell death. The hypothesis of "metabolic DNA" tries to explain this: probably, cells in the course of their vital activity constantly synthesize new DNA, increasing the number of copies of information so that it is more convenient to read it. Over time, DNA molecules wear out and cells release them into the environment along with metabolic products.
There is also an opinion that the release of vcDNA is a way for cells to exchange signals. For example, membrane vesicles containing small amounts of DNA were isolated from various intraorganizational fluids. Such bubbles can merge with cells, transferring DNA molecules to them.
They found DNA in my blood. Is it bad?
Extracellular DNA is a natural component of blood plasma, and it can be found in any person. Normally, its concentration is quite low, although it can vary, but in the case of pathological and stressful conditions, the amount of vcDNA increases sharply. For example, with burns or diseases associated with mass cell death, such as myocardial infarction or rheumatoid arthritis. Even in a healthy person, strong fluctuations in the level of vcDNA are possible if he is subjected to stress, for example, heavy physical exertion. However, after the load stops, the concentrations return to normal values.
The situation is more complicated with oncological diseases. It is not completely clear where the vcDNA originates from in this case – as a result of the death of healthy tissues or as a product of targeted isolation of tumor cells. Nevertheless, its quantity is also very different from the norm.
While medicine has not learned how to diagnose specific diseases by the concentration of vcDNA in the blood, however, it is already possible to assess the severity of the condition and predict the development of the disease.
So, if we compare the amount of vcDNA in people who have had a myocardial infarction, it turns out that the more vcDNA, the greater the complications and the risk of recurrent heart attack or cardiac arrest.
Perhaps a thorough study of the vcDNA sequences will help to make more accurate diagnoses. This is also the focus in the field of prenatal diagnostics: fetal cDNA is present in the mother's blood, which means that it is possible to obtain the genetic material of the child without surgery. This opens up a wide field for genetic analyses – to detect fetal diseases (for example, rhesus conflict) or to determine gender.
What do cells "think" about extracellular DNA?
Extracellular DNA is constantly present around cells, and it can be assumed that a change in its concentration or properties will serve as a signal to which other cells will respond.
An increase in the concentration of vcDNA has an activating effect on some cells. Cells of the immune system are able to trigger an immune response when recognizing vcDNA. This is due to a mechanism that is normally responsible for reacting to foreign molecules, such as viral DNA in the blood. The same receptors that recognize viral DNA also react to the body's own vcDNA, activating cells of the immune system.
For other cells, vkDNA can work as an alarm signal – a "witness effect" develops in them. Let's say we have a cell culture under stress: low oxygen levels, radiation exposure, or other abnormal conditions. In these cells, DNA is damaged and oxidative stress develops – aggressive substances accumulate that destroy the cellular contents. If the vcDNA isolated by the affected cells is transferred to the culture of healthy cells, then DNA damage and oxidative stress also begin to be detected in them. Such cells are called "witnesses" because they experience stress without being exposed to the initial factors.
However, this does not exhaust the effects of vcDNA: it can stimulate or slow down cell division, affect gene activity and protein synthesis. Apparently, vkDNA has a systemic effect on many cells, changing their physiology, but its specific nature remains mysterious.
What else do we (not) know about extracellular DNA?
Recently, there has been evidence that animal and human cells can absorb vcDNA from the blood. In some cases, these molecules reach the cell nucleus, penetrate inside and are embedded in the cell's own genome. Often, the integration of such a wandering vkDNA molecule into the genome ends with damage to the DNA of the recipient cell and its death. But if the embedding is successful, the information reading processes change: fragments of the former vkDNA block the work of genes in the cell nucleus or trigger the reading of their own information. Thus, we have a special mechanism of intercellular interaction – the exchange of genetic information.
This mechanism probably plays an important role in the development of diseases. A few years ago, the concept of "gene metastasis" was formulated: it is assumed that tumor cells can secrete multiple copies of their mutant genes. Healthy cells absorb them, integrate them into their genome and begin to produce mutant tumor proteins.
Similar processes can theoretically occur when cells of different organisms interact. Although fetal vcDNA is found in the mother's blood, there is no information about its absorption by cells yet. But it was found that during blood transfusion, not only the donor cells settle in the recipient's body, but also the donor's vcDNA can integrate into the recipient's cells.
Research on the functions of extracellular DNA has begun relatively recently, but we can already talk about the discovery of a fundamentally new mechanism of communication between cells within the body, and probably between organisms themselves.
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27.03.2017