How a cell untangles entangled RNA

Kirill Stasevich, "Science and Life"

Transposons, once in RNA, can confuse it so that it becomes useless for anything. But with DHX9, the problem is solved simply – it untangles the RNA, so now it can be put into action (figure from the press release of the Max Planck Institute of Immunobiology and Epigenetics Valuable waste).

As you know, only a small fraction of our DNA encodes proteins, and the main part of the genome does not seem to be needed. This supposedly unnecessary part was once called "junk" DNA – it was simply seen as a ballast that had accumulated for some reason over millions of years of evolution. However, no one really thinks so now – there are a lot of genetic elements in non-coding DNA that, even if they do not carry any protein information, still play a huge role in the life of the cell.

There are quite a lot of transposons in the "junk" DNA – this is the name of special sequences of nucleotides that jump from one place in the genome to another. There are several varieties of transposons. Some of them are moved using the "cut and paste" mechanism – the transposon physically leaves one place to insert itself into another part of the DNA. Others do otherwise, scattering their copies across the genome (the "copy and paste" mechanism). It is believed that at least part of the transposons originated from viruses that once got into the cell, and so remained in it.

Two mechanisms of transposition: the first (from above) is "cut and paste",
the second (from below) is "copy and paste" (illustration by Broad Institute).

In human DNA, one of the most numerous transposons are Alu elements that propagate through the "copy and paste" mechanism. There are more than 1.1 million copies of them, which in total makes up 10.7% of the human genome. Most of them are already inactive, that is, they don't "jump" anywhere, but those that are still working can cause big trouble.

It is easy to understand that if a transposon gets into some important gene, it will simply spoil it - and indeed, Alu elements can cause diseases such as hemophilia, breast cancer and some others. On the other hand, it is known that the same Alu elements are useful from an evolutionary point of view. Their sequences often stand side by side, so that between one transposon and another there is a gene or several genes.

The trick here is that such nearby transposons, when self-copying, also capture what is in between them. As a result, an extra copy of some gene appears in the genome, which can be freely changed as long as the "source" continues to perform the functions necessary for the body.

It is believed that it is thanks to the Alu elements that some monkeys - including those who were the ancestors of man – have regained the previously lost tricolor vision, that is, the ability to see blue, red and green. At some point, the transposons in the primate genome made a copy of the gene for the photosensitive protein opsin, and this copy subsequently "mastered" the third color.

That is, active transposons can be both good (helping a biological species acquire new successful properties) and bad (causing dangerous mutations). However, there may be one significant problem with both active and sleeping jumping sequences. Recall that DNA itself only stores information, and in order for this information to work, an intermediary molecule, RNA, is needed.

Relatively short RNAs are synthesized at different DNA sites, which serve as a template for the assembly of protein molecules. Due to the huge number of Alu elements in the genome, it often happens that RNA copied from DNA, in addition to the actual information nucleotide sequence, also carries transposon sequences. These sequences of transposons do not necessarily spoil the meaning of the main message, they can be, for example, on the sides of it, or in meaningless gaps between semantic pieces.

However, the problem is that the nucleotide sequences of Alu elements easily stick together. As a result, RNA turns from a more or less smooth, well-readable "thread" into an unreadable lump – molecular machines that prepare RNA for protein synthesis and that synthesize protein themselves simply cannot work with such a confused structure.

But the cage, of course, has tools for such a case. Researchers from the Institute of Immunobiology and Epigenetics Max Planck Societies write in their article in Nature about the DHX9 protein. This is a helicase, that is, an enzyme that untangles nucleic acids; there are many helicases, some of them specialize in DNA, others in RNA, and DHX9 belongs to those who work with RNA. If DHX9 is turned off, then those unreadable lumps of RNA will accumulate in the cell, and a shortage of those proteins, information about which is contained in entangled RNAs, will begin.

DHX9 purposefully recognizes Alu elements in RNA and untangles them. But if helicase worked alone, it probably wouldn't be so productive. DHX9 has at least one helper: a special protein that edits RNA – in other words, it chemically modifies the nucleotides that are included in the Alu sequence, and after such editing, the Alu elements become safe.

Of course, there naturally arises a proposal to get rid of Alu elements directly in DNA altogether - which would be more effective than monitoring the constantly synthesizing RNAs and unwinding those that turned out to be entangled. However, either it is too difficult to create such a molecular apparatus, or such transposons, despite all the troubles associated with them, represent an important source of genetic variability, which from an evolutionary point of view it would be foolish to abandon.

Of course, this is far from the only molecular trick that our cells had to invent in connection with transposons. For example, some time ago we talked about the fact that there are more than one and a half hundred proteins in the primate genome, whose task – at least before - was to keep the horde of transposons under control. 

Portal "Eternal youth" http://vechnayamolodost.ru  05.04.2017