A gene that keeps track of how often it’s made into a protein

Folks in the Baranov lab in County Cork, Ireland, were just reviewing old data they had lying around—you, know, as one does on a slow, boring afternoon—and they noticed something weird. The complexes within a cell that translate RNA into proteins were piling up at the end of the RNA, long past the portion that encodes the protein. Hmm.

Ribosomes and the genetic code

Many of the genes held in our DNA encode proteins. But the process of translating DNA into protein goes through an RNA intermediate. That RNA is read by a complex called the ribosome, which recognizes the information in the RNA and uses it to create a string of amino acids in a specific order—the protein encoded by the gene. So ribosomes play a critical role in gene activity.

To find out more about that role, ribosome profiling was developed in 2009. It allows researchers to identify which RNAs in a given cell are being translated by isolating only those RNAs with ribosomes attached. It also allows them to assess the relative levels at which different regions of RNA are being translated. Baranov's lab developed online genome browser for viewing ribosome profiling data in 2014.

When ribosomes translate an RNA molecule into protein, they move along an RNA and add one amino acid at a time to the growing protein as they go. When they hit a stop signal in the RNA, the protein is done. But these scientists in Ireland saw some ribosomes plowing right through the stop signal of the transcript for a  specific gene, down the tail of the RNA, and continuing until they hit the next stop signal.

To see what was going on, the researchers took out the first stop signal. Normally all of the ribosomes should go right to the second one, instead of only some of them. Instead, no more protein was made from the gene. They concluded that translation of the tail region serves to shut down this gene's activity.

Various experiments showed that translation of the tail region did not diminish the stability of the AMD1 protein, or cause it to be degraded, or cause it to be ejected from cell. Rather, they suggest that, as occasional, random ribosomes read through past the first stop signal, they hit the next one, and the ribosomes pile up. Once there are enough, the ribosomes physically impede translation of the whole RNA.

Translation and memory

A consequence of this is that the maximum number of proteins produced from one of these RNA molecules is going to be proportional to the number of ribosomes that have read it. That, in turn, is proportional to the number of proteins that have been made from it.

The RNA in question comes from the gene AMD1, which encodes an enzyme important in cell proliferation, embryonic stem cell renewal, and the development of neurons. Its dysregulation can lead to tumorigenesis, so it is under tight translational control; RNA made from this gene has a half-life of less than an hour, so protein levels are determined mainly by how quickly protein is translated during that time.

This ribosome stalling might provide a new layer of regulation, limiting the number of AMD1 molecules that can be generated from each RNA. Since it is tied to the number of ribosomes traversing the transcript, it would only kick in if translation was very high. High levels of translation could be problematic for a protein like this one. It is probably important, since the same ribosome pile-up was seen in mice, rats, fish, and frogs, and the mRNA tail goes back at least to the ancestor of vertebrates.

The researchers also found other RNAs that have ribosomes piled up at the stop signal just past the one that is normally used. It would be pretty cool if they have unraveled a new mode of regulating a process that we already thought we know a lot about.

Nature, 2018. DOI: 10.1038/nature25174 (About DOIs).