‘ZIP’ codes tell RNA molecules how to get to their designated locations
They say life comes without a manual, but that’s not quite true. Every cell in our body lives according to the instructions of its DNA in the form of RNA molecules. RNA was recently put in the spotlight as the basis of innovative COVID-19 vaccines, but much fundamental knowledge about this vital molecule — how it makes its way into the cell to a designated location, for example — is still lacking. Researchers at the Weizmann Institute of Science have now discovered a cellular “zip code” system that ensures that all RNA gets to the right place on time.
After the RNAs are produced in the nucleus, some stay there to regulate gene expression, but most — especially those with the protein recipes — are scheduled to leave the nucleus for the cytoplasm, where proteins are made. Previous studies to clarify how RNAs get to their assigned locations had yielded conflicting results. Some suggested that the pathways of the string-like, linear RNA molecules may be dictated by information in their loose ends. Still, some RNAs are circular and clearly have no ends. Other studies found evidence that certain short segments within RNA molecules might function as zip codes, defining the neighborhood in the cell where each RNA belongs, but several studies reported on different zip codes and there was limited understanding of how such zip codes might work.
Research student Maya Ron and Prof. Igor Ulitsky, both of the Departments of Immunology and Regenerative Biology and Molecular Neuroscience at the Weizmann Institute of Science, tested the zip code hypothesis using a technique known as a “massively parallel RNA assay,” developed in part. in Ulitsky’s laboratory. The technique makes it possible to study thousands of different RNAs simultaneously, with results obtained within days instead of the years it would previously have taken to study the same RNAs one at a time. The scientists inserted thousands of different RNA segments into various “host” RNA molecules — linear or circular — copies of which were then introduced into millions of cells. After separating the nucleus from the cytoplasm of these cells, the researchers were able to see where their RNAs had ended up.
After examining some 8,000 genetic segments in this way, Ron and Ulitsky discovered that a few dozen of them do indeed serve as zip codes. These zip codes instruct some RNAs to stay in the nucleus, tell others to enter the cytoplasm immediately, and instruct others to make this move only after being in the nucleus for a while. The researchers also discovered several proteins that serve as “postal officers” whose job is to bind to RNAs, “read” their zip codes, and ship the RNAs to the locations encoded there.
Remarkably, there was a clear separation between linear and circular RNAs within this ‘postal system’. For starters, the same zip code could map an RNA to a different location depending on whether it was linear or circular. In addition, two sets of postal workers performed the sorting, one for the linear RNAs and one for the circular ones. In fact, each of the clerks gave their own specific kind of instructions. For example, one protein, called IGF2BP1, bound mainly to linear RNAs, promoting their export from the nucleus. Another, called SRSF1, specialized in directing circular RNAs to stay in the nucleus. When the scientists blocked the activity of individual proteins, the RNAs sorted by each of these postal workers did not reach the correct locations in the cell.
These findings not only shed new light on how the genome works, but may also be useful in designing RNA-based therapies. “Many companies are now developing RNAs to use as drugs or vaccines,” Ulitsky says. “Understanding how they get to their locations in the cell can help develop artificial RNAs with desirable properties. For example, if we want an RNA drug to make large amounts of a particular protein, it can be designed to spend most of the time in the cytoplasm.” where this protein can be produced.”
The study’s findings may be particularly valuable for the use of circular RNAs, which have become the focus of research relatively recently and are less well understood than linear RNAs.
“In nature, only a small percentage of RNAs are circular, but they are more stable than linear and are therefore increasingly being used in drug design,” explains Ron.
Researchers develop the most comprehensive RNA atlas to date
Maya Ron et al, Context-specific effects of sequence elements on subcellular localization of linear and circular RNAs, nature communication (2022). DOI: 10.1038/s41467-022-30183-0
Quote: ‘ZIP’ codes tell RNA molecules how to reach their designated locations (2022, July 26) retrieved July 27, 2022 from https://phys.org/news/2022-07-codes-rna-molecules.html
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