Our cells have safety mechanisms that keep genetic parasites - such as viruses and transposons - in check while important genes of the host cell can remain active. Researchers have now shown that the molecular safety mechanisms of the host cell "smuggle" genetic information molecules around the cell, which are then used to recognize and shut down the parasites.
While information for the production of our cells' proteins constitutes less than two percent of our DNA, two-thirds of our DNA consists of selfish genetic elements such as retroviruses and tranposons and residues thereof. In fact, transposon sequences have benefited the adaptation of different species to new environments by imparting new regulatory elements to the genome. But unrestrained transposon proliferation makes the genome unstable and results in low fertility in both Drosophila, mice and humans.
The defence, which can shut down transposons, is guided by small RNA molecules, the so-called piRNAs. piRNAs are made in the cell from long RNA molecules that, after being produced within the cell nucleus, have to travel into the cytoplasm of specific piRNA production regions. However, the inherent problem is that the long RNA molecules - according to gene expression textbook dogmas in the field of RNA transport - should be locked inside the nucleus, as they lack all the molecular quality stamps that normally allow RNA to exit the nucleus.
Through their work, researchers have found that the transport of the long RNA molecules for piRNA production takes place via an until now unknown RNA transport route. This molecular route breaks with several of the traditional dogmas of RNA transport and thereby "smuggles" RNA that cannot pass the normal quality control in the cell into the cytoplasm and even delivers the long RNA molecules directly to the piRNA production regions.
This pathway requires Nxf3-Nxt1, a variant of the hetero-dimeric mRNA export receptor Nxf1-Nxt1. Nxf3 interacts with UAP56, a nuclear RNA helicase essential for mRNA export, and CG13741/Bootlegger, which recruits Nxf3-Nxt1 and UAP56 to heterochromatic piRNA source loci. Upon RNA cargo binding, Nxf3 achieves nuclear export via the exportin Crm1 and accumulates together with Bootlegger in peri-nuclear nuage, suggesting that after export, Nxf3-Bootlegger delivers precursor transcripts to the piRNA processing sites.
The study thus not only uncovers new insight about how animal genomes defend themselves against DNA parasites; it also reveals a glimpse of how cells sort and spatially distribute and organize genetic information. The authors have studied this problem in Drosophila, which is an ideal model system for this biology, which is expected to function in similar ways in humans.
Precisely this perspective, The senior author finds very interesting: "Although this important biology cannot currently be investigated in humans due to technical obstacles, we can explore the biological principles in model systems such as Drosophila. The framework of understanding we build here can in the future be combined with the enormous wave of genetic information the scientific community is receiving from patients worldwide these years. Therefore, our work can help translate the billions of sequences into meaningful biological information that can benefit people in the longer term."
piRNA export pathway discovered!
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