A crucial intermediate step on the way from the genetic code to the protein is the messenger RNA – a copy of the DNA that serves as a template for protein synthesis. In animals and plants, the mRNA goes through different processing steps by so-called RNA editors. Researchers have now succeeded in transferring the RNA editors from moss into human cell lines. There they unfold an astonishingly wide range of activities. While this is still unpredictable, further research could help modify the editors to allow for targeted, medically useful manipulations of the mRNA.
The blueprints for proteins are stored in the DNA of our genome. In order to implement these plans, our cells first make transcripts of the code in the form of so-called messenger RNA (mRNA). In some cases, however, these transcripts are not implemented immediately, but are initially processed further. Sometimes parts of the mRNA are cut out, sometimes individual building blocks, the so-called nucleobases, are exchanged. This so-called RNA editing ensures that templates for different proteins can be created from the same DNA sequence, each of which is precisely tailored to its respective place of use in the body.
differences in animals and plants
"RNA editing is very different in animals and plants," explains a research team led by Elena Lesch from the University of Bonn. In plants, the base cytosine is usually converted into the base uracil, while in animals the base adenosine is converted into inosine - each with consequences for the resulting protein. "It is not known whether these two different RNA editing methods are compatible with each other," say the researchers.
Another riddle: In plants, certain editing processes do not take place in the cell nucleus, but exclusively in the photosynthetic units, the chloroplasts, and in the cell's power plants, the mitochondria. "Although the so-called PPR proteins, which are responsible for RNA editing in plants, have evolved over 500 million years and exist in thousands of variants in some plant species, not a single PPR protein is known to work in the cell nucleus of plants ' the authors write.
Activity in the human cell nucleus
Are PPR proteins actually restricted to mitochondria and chloroplasts by some unknown type of barrier, or can they manipulate RNA elsewhere as well? To answer this question, Lesch and her colleagues transferred the RNA editing machinery from the moss Physcomitrium patens to human cell lines. And indeed: "It was shown that the editing mechanism of Physcomitrium patens also works in human cell lines," reports Lesch. With a processing efficiency of up to 91 percent, the PPR proteins from the moss mitochondria also exchanged bases in the mRNA in the nuclear genome of human cells.
To the researchers' surprise, the moss RNA editors even showed broader activity in humans than in Physcomitrium patens. The editor PPR56 has only two attack sites in the mRNA of the moss. In the cell nucleus of human cells, on the other hand, it was active in more than 900 different places. "There are significantly more different RNA transcripts of cell nuclear information in humans than RNA transcripts in the mitochondria of the moss," explains Lesch's colleague Mareike Schallenberg-Rüdinger. "It also gives editors a lot more targets to attack."
Approach for targeted manipulations?
So far, the researchers have not been able to predict exactly where the PPR proteins change the mRNA of human cells. In further studies, they now want to clarify the basic editing mechanisms. On this basis, it might be conceivable to optimize certain RNA editing factors in such a way that they only become active at selected targets and thus allow precise manipulations. "If we could correct defective spots in the genetic code using RNA editing methods, this would potentially also offer starting points for the treatment of hereditary diseases," says Schallenberg-Rüdinger. "Whether that works remains to be seen."
Source: Elena Lesch (University of Bonn) et al., Nucleic Acids Research, doi: 10.1093/nar/gkac752