For everything to go well in living cells, the genetic information must be correct. But unfortunately, errors in DNA accumulate over time due to mutations. Land plants have developed a particular mode of correction: they do not directly improve errors in the genome, but rather in an elaborate way in each individual transcript. Researchers at the University of Bonn have transplanted this moss-correcting machinery Physcomitrium patens into human cells. Surprisingly, the concealer began to work there too, but according to its own rules. The results have just been published in the journal Nucleic acid research. »
In living cells there is a lot of traffic like on a big construction site: In land plants, blueprints in the form of DNA are stored not only in the cell nucleus, but also in the powerhouses of the cell ( mitochondria) and photosynthesis units (chloroplasts). These blueprints contain building instructions for proteins that enable metabolic processes. But how is the plan information transmitted to the mitochondria and chloroplasts? This is done by creating transcripts (RNA) of the desired parts of the plan. This information is then used to produce the required proteins.
Errors accumulate over time
However, this process is not entirely smooth. Over time, the mutations have caused the accumulation of errors in the DNA that must be corrected to obtain perfectly functional proteins. Otherwise, the energy supply to the factories would collapse. At first glance, the correction strategy seems rather bureaucratic: instead of improving errors directly in the blueprint – the DNA – they are cleaned up in each of the many transcripts by so-called RNA editing processes.
Compared to letterpress printing, it would be like correcting every book by hand, rather than improving the printing plates. “Why living cells make this effort, we don’t know,” explains 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 succeeded in transplanting the RNA-editing processes of the moss Physcomitrium patens into the bacterium Escherichia coli. It has been shown that foam repair proteins can also modify the RNA of these bacteria.
Today, researchers from the Institute of Cellular and Molecular Botany, in collaboration with the team led by Prof. Dr. Oliver J. Gruss from the Institute of Genetics at the University of Bonn, went further: they transferred the RNA-editing machinery of the moss into standard human cell lines, including kidney and cancer cells, for example. “Our results showed that the corrective mechanism in land plants also works in human cells,” reports first author Elena Lesch. “It was previously unknown. »
But that’s not all: the RNA editing machines PPR56 and PPR65, which act only in the mitochondria of the moss, also introduce nucleotide modifications into the RNA transcripts of the cell nucleus of human cells.
Over 900 targets
Surprisingly for the research team, PPR56 makes changes to more than 900 attack points in human target cells. In moss, on the other hand, this corrector RNA 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 publishers to attack. Although editors follow particular code, at this stage it is not yet possible to accurately predict where the editing machines will make changes to human cells.
However, the abundance of RNA-editing targets in human cells also offers the opportunity to learn more about the basic mechanisms of proofreaders in further studies. This could be the basis for methods of inducing a very specific RNA change in human cells by means of a corrector. “If we could correct faulty sites in the genetic code with RNA editing methods, this would potentially also offer starting points for the treatment of hereditary diseases,” says Schallenberg-Rüdinger, looking to the future. “It remains to be seen whether this will work. »