To cap or not to cap: Scientists find new RNA phenomenon that challenges dogma

August 27, 2012 by Emily Caldwell

Some RNA molecules spend time in a restful state akin to hibernation rather than automatically carrying out their established job of delivering protein-building instructions in cells, new research suggests.

And instead of being a fluke or a mistake, the research suggests that this restful period appears to be a programmed step for RNA produced by certain types of genes, including some that control cell division and decide where proteins will work in a cell to sustain the cell's life.

This could mean that production in is not as clear-cut as biology textbooks suggest, scientists say.

"This could mean there are more variations to the proteins in our bodies than we realize; it means that RNAs can be stored and reactivated and we don't know what biological process that affects - it could influence , or , or even cancer," said Daniel Schoenberg, professor of molecular and cellular biochemistry at Ohio State University and lead author of the study.

Schoenberg and colleagues discovered this by tracing the origins of a cap-like structure on (mRNA) that is known to coordinate most of this RNA molecule's short life. Messenger RNA is manufactured in a cell's and each mRNA contains the instructions needed to produce a specific protein that a cell needs to live.

Until now, scientists have believed that once an mRNA is no longer needed to make protein, the cap comes off and the molecule is degraded, its job complete. But Schoenberg's lab discovered in 2009 that some mRNAs that were thought to be degraded were instead still present in the cell, but they were missing part of their sequence and had caps placed back on the newly formed ends. Because these mRNAs were in the , the changes had to happen there rather than inside the nucleus.

In this new study, the researchers were looking for further evidence of these apparent rogue mRNAs, but instead they found that a completely unexpected biological process occurs before some proteins are even a glimmer in a gene's eye: The uncapping and recapping of mRNAs outside the nucleus results from a cap recycling operation in the cell cytoplasm. This process appeared to enable certain RNAs to pause, without being degraded, before launching protein production.

"What this discovery tells us is a complete fundamental reworking of the relationship between a gene, messenger RNA and a protein. It's more complicated than we realize," Schoenberg said.

The research is published online in the open-access journal Cell Reports.

That fragments of mRNA could exist at all in the cell's main body was first reported by other scientists in 1992. Years later, Schoenberg asked a postdoctoral researcher in his lab to revisit these unexpected RNA fragments and confirm they exist. The postdoc's experiments showed that these mRNA, thought to be the dregs left over from their degradation, had caps on them - suggesting they still had the potential to function in . Schoenberg, also director of Ohio State's Center for RNA Biology, has been investigating this cytoplasmic capping operation ever since.

In 2009, he and colleagues reported the discovery of two enzymes in the cell's main body that would enable mRNA capping to occur completely outside the nucleus and in the cytoplasm instead.

In the current studies, Schoenberg sought to determine the physiological significance of this capping operation. The researchers engineered a way to block cytoplasmic capping in cells in the lab and then looked at changes in more than 55,000 RNAs.

This interference with cytoplasmic capping revealed that two different types of pathways could exist in the cells - some mRNAs remained stable without their caps, while others without caps were rapidly destroyed. This finding indicated that mRNAs can lose their caps in the cytoplasm and at some point get recapped. With further experimentation, the researchers determined that only some mRNAs lost their caps in the cell body.

"It's not all of any particular message that's uncapped, just a portion of a message," Schoenberg said. "We wanted to show that we have uncapped RNAs in the cell and they are not degraded. It means they're stored that way."

This finding offered hints that there is a higher order to this phenomenon, and that some mRNAs purposefully rest in an uncapped state without being degraded by enzymes within the cell whose job is to remove them. It also suggested that as the capping circumstances change inside the cell body, signals from genes might undergo change that allows for two or more proteins, one being shorter than the other, to be made from the same mRNA.

"We have always thought that one gene would give an mRNA for one kind of protein. But what we have found makes us wonder if multiple proteins could be made from each of the messenger RNAs that undergo decapping and recapping in the cytoplasm," Schoenberg said.

The researchers used bioinformatics technology to determine which genes were manufacturing mRNAs that could exist in this uncapped and recapped state in the cytoplasm. These included those that control some of the most basic elements of cell survival: They determine the location of proteins and RNAs within the cell and, perhaps most significantly, the mitotic cell cycle - part of the process of cell division.

"It wasn't random. It was very specific," Schoenberg said. "There are specific families of mRNAs that are regulated in this way, and that has ramifications for how proteins are expressed and regulated."

As an example, he cited how neurons communicate messages across vast distances to other nerve cells. It is known that mRNAs are deliberately kept in a silent state while they travel from, for example, the spinal cord to the fingertip, where they are then activated to make new proteins.

"What would the condition be of the to keep it silent? The possibility is it doesn't have a cap on it, and if it doesn't, it can't be translated. Maybe cytoplasmic capping in neurons is a function that allows that message to be translated at just the right time," Schoenberg said.

Or, in the case of cancer: "What if one of the things that happens is you are making shortened proteins instead of full-length proteins and the regulatory part of the protein is missing in the shortened protein? If that's true, can you interfere with this process and interfere with malignancy as a result?"

For now, these scientists can only speculate about what this unexpected really means. Schoenberg's lab plans to investigate the phenomenon more thoroughly in a line of breast cancer cells.

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1 / 5 (2) Aug 27, 2012
hell yea. massive discoveries upending traditional models. i like it.

ever since i heard the term Junk DNA 20 years ago, I intuitively understood that science is a process based on accepting ignorance of the cause, and that 'science' as a subject of study is often problematic as it states to know things that it does not always know. with "junk dna" is was intuitively clear that the 'subject' writers were asserting something absurd rather than saying they simply did not know what this dna was for.

there is much much much more for us to learn about rna. I for one am not buying any rhetoric that we are even close to understanding the entirety of how basic cellular processes work. We have only begun to finish the first stage of cellular exploration using the simplest and first few decades of tools that biology has afforded us.

not rated yet Aug 27, 2012
They are probably as most always confusing the sequence hypothesis (DNA -> RNA -> protein) which is the general flow of genetic information, with Crick's "central dogma", that once genetic information has been coded into a protein it is observed that it doesn't get back out again. http://en.wikiped..._biology

As such this is another nice test of the important, but not really dogmatic, dogma.
not rated yet Aug 27, 2012

"I called this idea the central dogma, for two reasons, I suspect. I had already used the obvious word hypothesis in the sequence hypothesis, and in addition I wanted to suggest that this new assumption was more central and more powerful. ... As it turned out, the use of the word dogma caused almost more trouble than it was worth.... Many years later Jacques Monod pointed out to me that I did not appear to understand the correct use of the word dogma, which is a belief that cannot be doubted. I did apprehend this in a vague sort of way but since I thought that all religious beliefs were without foundation, I used the word the way I myself thought about it, not as most of the world does, and simply applied it to a grand hypothesis that, however plausible, had little direct experimental support." [Crick, Wp.]
not rated yet Aug 27, 2012
[cont] Of course since then much more experiments have been done, this successful test was one of them

What they have discovered appears to be another epigenetic pathway, of which many are known. And the one gene-one protein idea was never part of this, and eukaryotes especially is C&P genetic material to make a large set of genes with so called alternative splicing. http://en.wikiped...splicing

The oversell, especially by biologists, is shameful.

@ Jeddy_Mctedder:

While it always nice with large discoveries, this isn't one of them. RNA silencing in general, especially affecting mRNA, is old hat. http://en.wikiped...ilencing

It has nothing to do with what is now called "genetic dark matter", and all to do with gene expression.
1 / 5 (1) Aug 27, 2012
IMO most of "junk DNA" is used for eating and powering of immune separate. To be able to deactivate/dissolve most of proteins of all potential parasites/prey, you should have appropriate specialized proteins for it. This is an evolutionary strategy of seemingly primitive protozoa or lancelets, whose evolution at morphological level stopped due their passive and hidden way of life, but which they still have a huge genome, because they're able to eat everything and they're able to fight with every bacteria. Also, to be able to use such a proteins fast, they should have the corresponding RNA prepared and activated for it.
not rated yet Aug 27, 2012
As I said, very little genetic dark matter has to do with gene expression, IIRC at most 5 % in surveys. Most of it is not used (say, pseudogenes no longer used and slowly degrading) or genetic parasites. It is an open question if this dark matter has specialized in anything, AFAIK.

Similarly it is an open question whether protozoa or lancelets, none of them "primitive" but branching early relative to us, have specific functions AFAIK. Certainly parasites while having in general a simple body plan can have complex life cycles.
1 / 5 (1) Aug 27, 2012
Maybe we should reconsider the genetic dark matter in the light of embryological parallelism. During development from embryo to adult, animals go through stages resembling or representing successive stages in the evolution of their remote ancestors. For example, if the human embryo has a gills in certain period of its development, then it must have sleeping genes for it too. With respect to the adaptive flexibility of species it may be advantageous not to forget all features, which were invented during evolution in the past. From the same reason the source codes of large SW projects often contain volume of commented out fragments of code: it's easier to revive them at the case of urgent change of customer need, than to develop them again.
not rated yet Aug 27, 2012
@ ValeriaT:

quoting: "During development from embryo to adult, animals go through stages resembling or representing successive stages in the evolution of their remote ancestors. For example, if the human embryo has a gills in certain period of its development, then it must have sleeping genes for it too."

It seems that you are refering to the biogenetic law, which implies that embryos go through adult stages of ancestors, which is purely wrong. This is a generalisation and can ONLY apply to very few cases.

As for human embryos having gills is fully incorrect again. Human embryos transiently form structures, which in fish develop into the gills of adults, but in the embryos of both fish and human these structures are NOT gills; they are called pharyngeal arches and pouches. In humans their numbers are far more reduced, and those that form the fish gills per se, form bits of the hyoid bone and laryngeal cartilages/ligaments in humans. So, human embryos do not have gills :)
1 / 5 (1) Aug 28, 2012
This doesn't really upend the entire dogma of genes-proteins science.

I'm thinking this may be a good indication of how some bizarre auto-immune diseases appear suddenly and go into remission suddenly at times.
not rated yet Aug 28, 2012
I wouldn't say it upends anything - it just says our picture is not complete (upending would mean that the previous thought mechanisms do not apply anymore AT ALL - and that is not the case)

As always in science: you try the simplest model first. Then you discover complications so you have to augment the model. From a scientific standpoint this is 'business as usual'. (Yes: exciting discoveries are 'business as usual' in science. That's why doing it is so much fun.)
not rated yet Aug 28, 2012
@ ValeriaT:

The so called "recapitulation" has been known to be wrong for decades. Due to developmental constraints there is a bottleneck, meaning the fetus looks much the same for widely branched animals. All development is under genetic control, and genes aren't part of dark matter.

See the numbers, a small percent of genetic dark matter is affecting gene expression. You can't get around that observation. [Ref: It's walked through the blog Genomicron IIRC, science blogging by a genetics expert.]

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