Upcycling of proteins protects DNA from parasites
Of the three billion base pairs in the human genome, less than two percent contain information encoding the ~20,000 proteins. Indeed, at least half of our genetic material comes from selfish genetic elements such as transposons. Scattered in the genomes of plants, fungi and animals, transposons can "jump" from one genomic position to another. In doing so, they are an important source of genetic diversity and can thus help their host adapt. On the other hand, uncontrolled transposon activity leads to widespread DNA damage and mutations, which can lead to cell disease or death. To prevent this, organisms have developed effective ways to control harmful intruders in the genome.
Julius Brennecke's laboratory at IMBA is studying a small RNA-based immune system in the genome that suppresses transposal activity in animals. Pi RNAs are treated from longer RNAs, which must leave the cell nucleus to go to pi RNA production sites in the surrounding cytoplasm in order to go to pi RNA production sites. But there is a problem: the nucleus has a quality control system to prevent RNAs that do not have molecular maturation signatures from moving to the cytoplasm - and pi RNA precursors lack all these molecular signatures. It has therefore remained a mystery how pi-RNA precursors pass through cellular safety controls and leave the nucleus to provide the cell with the pi-RNAs essential for genomic defence.
A unique cellular travel itinerary for piRNAs
Peter Refsing Andersen, former postdoctoral fellow at IMBA and now group leader at the University of Aarhus in Denmark, recently discovered that cells bend conventional transcription rules when they manufacture pi RNA precursors. piRNA loci, which resemble genome transposon cemeteries, are integrated into heterochromatin, a form of chromatin that generally prevents transcription. However, the cells reverse the repressive character of heterochromatin at the piRNA loci, which makes it possible to transcribe them. Today, Peter and Mostafa ElMaghraby-a doctoral student at the Vienna BioCenter PhD - show that emerging RNA pi precursors also use heterochromatin to allow the nucleus to travel to their cytoplasmic destination. A protein called Nxf3, a sister protein to the exporter of Nxf1 RNA, plays a central role in this process. Nxf3, with his companion Bootlegger, smuggled the precursor of RNA pi from heterochromatic production sites into the cytoplasm, where he then delivered the RNA shipment to the pi RNA production machine. "The Nxf3 pathway bypasses cell quality control points and reveals a new concept of epigenetically coded "routes" to sort genetic information in cells. It is fascinating to see how cells use existing building blocks to build new roads, which face the challenges of evolution. Just as furniture can be reused with IKEA hacks," explains Peter Refsing Andersen, the first co-author of this new publication.
A travel guide that has become a guardian of the genome
Meanwhile, the Brennecke group has revealed that Nxf2, another Nxf1 sister protein, is also an essential component of the transposon cell defense system. Surprisingly, Nfx2 has lost its function as the RNA's "travel guide" and plays a central role in the formation of heterochromatin at transposal sites. Such heterochromatin formation protects the genome by preventing transposons from jumping. "This is the first demonstration of an RNA export protein performing a completely different task from its original function," explains Julia Batki, who with Jakob Schnabl studied the Nxf2 function during her studies in the Vienna BioCenter doctoral program.
As evolution progresses, existing structures are often duplicated and then converted into something new that could be useful. Our results present a remarkable example of "adaptive radiation" at the protein level. Two copies of the ancestral RNA exporter were reused during evolution to perform entirely new functions in the cell. Especially in an arms race such as the one against rapidly evolving genome parasites, it could be very beneficial to quickly innovate new molecular pathways that help to keep ahead of genetic competitors," said Julius Brennecke, head of the IMBA group.
