Scientists discover RNA modifications in some unexpected places

The so-called central dogma of molecular biology—that DNA makes RNA which makes protein—has long provided a simplified explanation for how genetic information is deciphered and translated in living organisms.

In reality, of course, the process is vastly more complicated than the schema first articulated nearly 60 years ago by Nobel Laureate Francis Crick, co-discoverer of the DNA's double-helix structure. For one, there are multiple types of RNA, three of which—messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA)—are essential for proper protein production. Moreover, RNAs that are synthesized during the process known as transcription often undergo subsequent changes, which are referred to as "post-transcriptional modifications."

Multiple such RNA modifications have been documented over the years, although the precise functions and significance of many of these have been shrouded in mystery. Among the most common post-transcriptional modifications is pseudouridylation, during which the base nucleoside uridine—the 'U' of the four base RNA nucleosides abbreviated as A, C, T, and U—has its chemical structure altered to form a molecule known as pseudouridine (ψ). To date, ψ has been found in abundance in tRNA, rRNA, and small nuclear or snRNA, but was thought not to exist in mRNA.

Until now.

Deploying sophisticated high-throughput sequencing technology, dubbed ψ-seq, a team of Whitehead Institute and Broad Institute researchers collaborated on a comprehensive, high-resolution mapping of ψ sites that confirms pseudouridylation does indeed occur naturally in mRNA. This somewhat surprising finding and the novel approach that led to it are revealed online this week in the journal Cell.

"This is really a better, more quantitative method to measure this modification, which is interesting in and of itself," says Douglas Bernstein, a co-first author of the Cell paper. "Finding the modification in mRNA was an unexpected bonus."

Bernstein, a postdoctoral researcher in the lab of Whitehead Institute Founding Member Gerald Fink, collaborated with postdoc Schragi Schwartz and Max Mumbach in the lab of Broad Institute Core Member Aviv Regev to orchestrate the ψ mapping in yeast. Having discovered pseudouridylation at dozens of sites in mRNA, the group set out to determine the functional role of the modification.

Knowing that pseudouridylation is catalyzed by enzymes known as pseudouridine synthases (PUS) the group looked for differences in mRNA pseudouridylation between a normal, wild-type yeast strain and a mutant strain with a PUS gene deleted. Intriguingly, heat shock dramatically increased the number of mRNA pseudouridylation sites in the normal strain but not in the . Further, the group found that pseudouridylated genes were expressed at roughly 25% higher levels in the wild type strains than in the genetically modified strains.

Taken together, these findings suggest that heat shock activates a dynamic pseudouridylation program in yeast that may lead to beneficial outcomes for the organism, perhaps by increasing mRNA stability under adverse conditions.

While the research begins to outline a role for pseudouridylation of mRNA in yeast, its methodology and findings are likely to have implications in humans as well. As part of this work, the scientists performed ψ-seq on a line of human cells as well, finding remarkable similarity in mRNA pseudouridylation sites between human and yeast cells. Notably, a number of human diseases, including dyskeratosis congenita, which is characterized by a predisposition to cancer and bone marrow failure, are associated with mutations in PUS genes, suggesting that ψ-seq may have applications in uncovering the significance of RNA pseudouridylation in human pathologies.

Explore further

New mechanism in gene regulation revealed

More information: "Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA" Cell, September 11, 2014. … -8674%2814%2901098-8
Journal information: Cell

Citation: Scientists discover RNA modifications in some unexpected places (2014, September 15) retrieved 16 June 2019 from
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

Feedback to editors

User comments

Sep 15, 2014
Nitpick: That isn't Krick's central dogma from 1958, that is the simplistic Watson version.

"According to Crick, the correct, concise version of the Central Dogma is ...
... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)"

"Unfortunately, there's second version of the Central Dogma that's very popular even though it's historically incorrect. This version is the simplistic DNA → RNA → protein pathway that was published by Jim Watson in the first edition of The Molecular Biology of the Gene (Watson, 1965). ...

If the Watson pathway version of the Central Dogma really was the one true version then it would have been discarded or modified long ago. "

[ http://sandwalk.b...ogy.html ]

See how Krick's 1958 figures detail the apriori possible and the a posteriori permitted. Among them these post-transcriptional modifications.

Sep 17, 2014
To the innocent public: don't mind the anti-science pheromone troll, who is ultimately spamming for his junk drug $$$ite.

Evolution is plenty evidenced, no other processes (say, pheromone "control") are.

Sep 17, 2014
The links I provided were to articles published in Science. Both were "Perspective" articles.

What kind of under informed theorist tells others
Evolution is plenty evidenced...
but refuses to address the current perspectives that clearly link RNA-mediated events to cell type differentiation in all species via my nutrient-dependent pheromone-controlled atoms-to-ecosystems model when no evolutionary event has ever been described that links one species to another via biologically-based cause and effect?

"We cannot conceive of a global external factor that could cause, during this time, parallel evolution of amino acid compositions of proteins in 15 diverse taxa that represent all three domains of life and span a wide range of lifestyles and environments. Thus, currently, the most plausible hypothesis is that we are observing a universal, intrinsic trend that emerged before the last universal common ancestor of all extant organisms." --Jordan et al (2005)

Sep 17, 2014
To the innocent public: don't mind the anti-science pheromone troll, who is ultimately spamming for his junk drug $$$ite.

Evolution is plenty evidenced, no other processes (say, pheromone "control") are.

T L.
Do you know of Erik Andrulis at Case Western?

Sep 17, 2014
Until 'evolution' is defined as something more than 'change over time' or whatever other vague phrases are used to avoid acknowledging claims that RNA-mediated events link ecological variation to ecological adaptations via conserved molecular mechanisms of cell type differentiation in species from microbes to man, Erik Andrulis and all other theorists -- no matter how talented they are -- will be stuck trying to link an evolutionary event to anything that makes sense.

For contrast, look at this: Starvation-Induced Transgenerational Inheritance of Small RNAs in C. elegans http://www.cell.c...)00806-X

Ask yourself why it comes from people who claim: http://www.odedre...out.aspx "Our principle aim in the lab is to attack scientific dogmas. Mainly, we aim to use powerful genetic tools to discover novel biological principles by which RNA affects formation and inheritance of complex traits."

What they are doing is attacking theory with facts.

Sep 17, 2014
"Differences in the behavior of nematodes are determined by nutrient-dependent rewiring of their primitive nervous system (Bumbarger et al., 2013). Species incompatibilities in nematodes are associated with cysteine-to-alanine substitutions (Wilson et al., 2011), which may alter nutrient-dependent pheromone production."

Nutrient-dependent/pheromone-controlled adaptive evolution: a model

It has become obvious RNA-mediated events, which lead to the amino acid substitutions that differentiate cell types, are linked to differences in behavior of different species via their pheromone-controlled physiology of reproduction. That's how amino acid substitutions are fixed in the organized genomes of species from microbes to man.

Looking at morphology and claiming differences somehow 'evolved' without explaining fixation is something that is only still done by pseudoscientists and those taught to believe in their ridiculous theories.

Sep 17, 2014
Why is it you can't understand that all those "nutrient dependent, pheromone controlled" adaptations ARE the very basic description of evolution? Mutations require adaptation, you idiot...

Sep 17, 2014
Thanks for asking.

Mutations perturb protein folding that might otherwise lead to ecological adaptations and increasing nutrient-dependent pheromone-controlled organismal complexity, which arises via controlled RNA-mediated events.

Why can't you grasp biological facts that link ecological variation to the ecological adaptation of teeth in nematodes and the ecological adaptations in the teeth of sticklebacks and humans via conserved molecular mechanisms?

Has someone told you about an evolutionary event that links mutations to morphological and to behavioral phenotypes? That's a requirement for ecological speciation. Is it not also required in speciation attributed to mutations, natural selection, and evolution?

If no concurrent changes in behavior are required, researchers may not be joking about the evolution of teeth in sticklebacks. http://newscenter...olution/

Do you know how teeth evolve in fish?

Sep 18, 2014
Why can't you grasp biological facts
this is hilarious considering that you cannot even comprehend that your own model creates mutations... so when you say
Mutations perturb protein folding that might otherwise lead to ecological adaptations
which is essentially anti-mutation speak, but then turn around and talk about your model, which causes mutations, you look like the uneducated lab tech that you are
remember when I asked
DOES your model make any changes to the nucleotide sequence of the genome of an organism, virus, or extrachromosomal genetic element?
This is a yes or no answer
THIS IS THE DEFINITION OF MUTATION - to which you answered
--Thanks for asking
so your continued diatribe against mutation only proves that you are far more illiterate and ignorant of "biological facts" than anyone else here

Lenski proves mutation as well as Evolution
you only prove (consistently) that you are willing to ignore reality for your religion (stupidity)

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more