Repair schedule
The cell repairs DNA by the hour
Kirill Stasevich, "Science and Life" based on the materials of Medicalexpress: Could reading our circadian clocks according to DNA repair optimize chemotherapy?
We do not get tired of talking about how great the role of biological clocks in our lives is: our sleep depends on them, they affect the immune system, metabolism, heart function, etc., etc. And if we go down a few levels lower, to nucleic acids and proteins, then we will see that even the main molecular processes obey the circadian rhythms, without which no cell can do.
Aziz Sanjar and his colleagues from the University of North Carolina at Chapel Hill describe in their article in PNAS the relationship between biological clocks and DNA repair (Yang et al., Cisplatin-DNA adduct repair of transcribed genes is controlled by two circadian programs in mouse tissues). Perhaps many people remember that Sanjar was one of the three laureates of the 2015 Nobel Prize in Chemistry – then it was given just for DNA repair, more precisely, for deciphering the molecular mechanisms by which a cell corrects defects in DNA.
Excision repair of nucleotides (repair "according to Sanjar) – a whole piece with a genetic defect is cut out of DNA. Illustration of the Nobel Committee.
Although DNA, as we know, is an extremely strong and stable molecule, mutations still occur regularly in it: DNA chains break, and other, incorrect letters appear in place of the correct genetic letters. Therefore, the repair mechanisms are very important, and therefore they work almost non-stop.
But, as it turned out, the activity of DNA repair machines depends on the time of day. Researchers experimented with cisplatin, a special platinum compound that, when combined with DNA, spoils its structure: strong chemical bonds (crosslinking) arise due to cisplatin both between chains and within the same DNA chain.
Recall that both chains in a double-stranded DNA molecule are normally connected to each other by hydrogen bonds, which are quite easy to break. And it is often necessary to break the links between the chains: molecular machines that read genetic information can do this only if the DNA chains are disconnected. Because of the rigid, unbreakable bonds between DNA chains, the cell begins to have problems: it can neither synthesize proteins nor divide.
To synthesize a protein, you first need to take a copy of the gene in the form of a matrix RNA molecule, and only then on the matrix RNA protein synthesizing machines will assemble the polypeptide chain of the protein. But to make a copy of RNA, you need to split the double-stranded DNA, and then special transcribing proteins (transcription is called RNA synthesis on a DNA template) will be able to assemble an RNA molecule.
If a cell wants to divide, then first it needs to replicate, that is, make new copies of DNA, and in order to synthesize new DNA, it is necessary again to divide the chains of the old one. If there are strong crosslinking within one chain, then again everything is bad: with such nucleotides (genetic letters), replication and transcription enzymes again cannot work.
Experimental mice were given cisplatin for 24 hours, while simultaneously tracking where in the genome DNA repair systems would correct cisplatin defects. As a result, it was possible to find almost 2000 genes on which the repairing enzymes worked differently at different times of the day, moreover with some peculiarities.
We just said that when an RNA copy is synthesized on a gene, the double-stranded DNA is unwound – but only one of its chains serves as a template for RNA synthesis. So, if we are talking about the chain from which a copy of RNA is removed, then the cell most actively repairs such chains before dawn or before sunset, depending on the specific gene.
But the other, non-transcribed chain, repair machines are engaged in before sunset, regardless of which gene it is. It is worth clarifying that DNA repair also goes on the rest of the time, it just becomes especially active at some hours, and such periods of activity, as it turned out, clearly obey the circadian rhythms.
We have repeatedly talked about how biological clocks work (by the way, they also gave the Nobel Prize for the molecular mechanism of biological clocks – last year). It is obvious that physiological changes corresponding to circadian rhythms could not occur if there were no circadian changes in the corresponding genes, and indeed, now we already know a lot of genes that are activated by the clock. It can be assumed that the activity of repairing systems is subject to the schedule of those genes that they repair; however, without additional experiments, it is too early to draw any far-reaching conclusions here.
And, of course, it is impossible not to note here the extremely great practical significance of the results obtained. Perhaps someone noted to himself that the authors of the work used in their experiments a substance that is used against malignant tumors.
Cisplatin can really kill a variety of cancer cells – because of the defects in the DNA that it causes, they can neither divide nor lead at least some kind of active life. The problem, however, is that ordinary cells are extremely affected by cisplatin, and the liver, kidneys and nervous system are particularly affected by it. It is possible that healthy tissues can somehow be protected from it if therapy is applied taking into account the diurnal features in DNA repair systems; it is possible that its effect on cancer cells can be enhanced if the biological clock in tumors is turned off. It is possible that this approach can be used not only in the case of cisplatin, but also with other therapies, and not only with cancer, but also with other diseases.
In fact, doctors are now more and more actively engaged in chronobiology, however, according to Aziz Sanjar himself, until now most of the work in this field has stopped only on the external manifestations of circadian rhythms: the patient received medicine, and depending on the time of day, he noted a more or less strong improvement; the mechanism of the phenomenon remained behind the scenes. But in order to fully benefit medically from our biological clocks, we need to know their mechanism in all molecular details, and it is studies like the one described above that bring us closer to this.
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