To exit the nucleus, ordinary RNA cargo must submit to rigorous quality control procedures. Transposon-silencing RNA, however, avoids all that. In fact, transposon-silencing RNA—PIWI-interacting RNA (piRNA)—takes an entirely different route, one that bypasses the usual gatekeepers. This route, newly discovered by scientists based at Aarhus University (Denmark) and the Institute of Molecular Biotechnology (Vienna, Austria), not only broadens our view of RNA export, it also enriches our knowledge of how genomic integrity is maintained. More generally, it gives us a glimpse of how cells sort and spatially distribute and organize genetic information.

The alternate RNA transport route was described in a paper (“A Heterochromatin-Specific RNA Export Pathway Facilitates piRNA Production”) that appeared August 8 in the journal Cell. According to this paper, unprocessed piRNA precursor transcripts use a bypass strategy similar to that used by retroviruses.

Retroviruses circumvent nuclear RNA surveillance systems by utilizing host NXF1-NXT1, a hetero-dimeric mRNA export receptor. The piRNA precursors rely on an Nxf1-Nxf1 variant called Nxf3-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,” the Cell article indicated. “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.”

This RNA transport route amounts to a safety mechanism that can keep genetic parasites—such as viruses and transposons—in check while important genes of the host cell can remain active. It helps distribute piRNA precursors around the cell, which are then processed into piRNAs that complex with PIWI proteins. These complexes recognize and shut down the genetic parasites’ offending transcripts.

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 from the adaptation of different species to new environments by imparting new regulatory elements to the genome. But unrestrained transposon proliferation can destabilize the genome. It can also reduce fertility, an effect observed in various organisms, such as fruit flies, mice, and humans.

Transposon control attracted the interest of Aarhus University’s Peter Refsing Andersen, PhD, who started as a postdoc five years ago at the Institute of Molecular Biotechnology (IMBA) but is now building his own group at Aarhus University. Now an assistant professor, Anderson is one of the corresponding authors of the current study. The other corresponding author is Julius Brennecke, a senior scientist at IMBA.

These scientists and their colleagues 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.

To establish the new findings, the scientists relied on the Drosophila model. “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,” Andersen noted. “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. Therefore, our work can help translate the billions of sequences into meaningful biological information that can benefit people in the longer term.”

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