In order for everything to run smoothly in living cells, the genetic information has to be right. Unfortunately, errors in the DNA caused by mutations accumulate over time. Land plants have developed a peculiar correction mode: they do not correct the errors directly in the genome, but laboriously in each individual transcript. Researchers at the University of Bonn transplanted this correction machinery from the moss Physcomitrium patens into human cells. Surprisingly, the proofreader also began to work there, but according to his own rules. The results have now been published in the journalNucleic Acid Research.”
In living cells, there is a lot of traffic, like on a large construction site: In land plants, building plans in the form of DNA are not only stored in the cell nucleus, but also in the power plants of the cell (mitochondria) and the photosynthesis units (chloroplasts). These blueprints contain building instructions for proteins that enable metabolic processes. But how is the blueprint information passed on in mitochondria and chloroplasts? It does this by making transcripts (RNA) of the desired parts of the blueprint. This information is then used to make the required proteins.
Mistakes accumulate over time
However, this process does not run entirely smoothly. Mutations have accumulated errors in DNA over time that need to be corrected in order to have properly functioning proteins. Otherwise the energy supply in plants would collapse. At first glance, the correction strategy seems rather bureaucratic: instead of correcting the glitches directly in the blueprint – the DNA – they are corrected in each of the many transcripts using so-called RNA editing processes.
Compared to letterpress printing, it would be like correcting each individual book by hand instead of improving the printing plates. “We don’t know why living cells go to this length of effort,” says Dr. Mareike Schallenberg-Rüdinger from the Institute for Cellular and Molecular Botany (IZMB) at the University of Bonn. “Presumably, these mutations increased as plants spread from water to land during evolution.”
In 2019, the IZMB team led by Prof. Dr. Volker Knoop to transplant RNA editing processes from the moss Physcomitrium patens into the bacterium Escherichia coli. It was found that the moss repair proteins can also alter the RNA of these bacteria.
Now researchers from the Institute of Cellular and Molecular Botany together with the team around Prof. Dr. Oliver J. Gruss from the Institute for Genetics at the University of Bonn went one step further: they took the RNA editing machinery from the moss into normal human cell lines, including kidney and cancer cells, for example. “Our results showed that the land plant correction mechanism also works in human cells,” reports first author Elena Lesch. “That was previously unknown.”
But that’s not all: The RNA editing machines PPR56 and PPR65, which only act in the mitochondria of the moss, also introduce nucleotide changes in the RNA transcripts of the cell nucleus in human cells.
More than 900 destinations
To the research team’s surprise, PPR56 makes changes to more than 900 sites in human cell targets. In the moss, on the other hand, this RNA corrector is only responsible for two correction sites. “There are many more nuclear RNA transcripts in human cells than mitochondrial transcripts in moss,” explains Dr. Mareike Schallenberg-Rüdinger. “As a result, there are also many more targets for editors to attack.” Although the editors follow a specific code, it is not yet possible to predict exactly where the editing machines will make changes to human cells at this time.
However, the abundance of RNA editing targets in human cells also offers the opportunity to find out more about the basic mechanisms of the correctors in further studies. This could be the basis for methods to bring about a very specific change in the RNA in human cells using a corrector. “If we could use RNA editing methods to correct defective areas in the genetic code, this would possibly also offer starting points for the treatment of hereditary diseases,” says Schallenberg-Rüdinger, looking to the future. “It remains to be seen whether that will work.”
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