Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists discover RNA modifications in some unexpected places

16.09.2014

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 mutant strain. 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.

###

This work is supported by the National Institutes of Health (grants GM035010 and 1F32HD075541-01), the National Human Genome Research Institute (grants P50HG006193 and U54HG003067), the Howard Hughes Medical Institute, Broad Institute Funds, the Marie Curie IOF, and the Swiss National Science Foundation.

Written by Matt Fearer

Gerald Fink's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

Full Citation:

"Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA"
Cell, September 11, 2014 (online)

Schraga Schwartz (1), Douglas A. Bernstein (2), Maxwell R. Mumbach (1), Marko Jovanovic (1), Rebecca H. Herbst (1,3), Brian X. Leo´n-Ricardo (1,4) Jesse M. Engreitz (1), Mitchell Guttman (5) Rahul Satija (1), Eric S.Lander (1,3,6) Gerald Fink (2,6), and Aviv Regev (1,6,7)

1. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
3. Department of Systems Biology, Harvard Medical School, Boston, MA 02114, USA
4. Department of Biology, University of Puerto Rico, Rio Piedras Campus, San Juan 00931, Puerto Rico
5. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
6. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
7. Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA

Matt Fearer | Eurek Alert!
Further information:
http://www.mit.edu

Further reports about: Biology Biomedical Medical RNA mRNA modification modifications strain structure

More articles from Life Sciences:

nachricht Polymers Based on Boron?
18.01.2018 | Julius-Maximilians-Universität Würzburg

nachricht Bioengineered soft microfibers improve T-cell production
18.01.2018 | Columbia University School of Engineering and Applied Science

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

Im Focus: A thermometer for the oceans

Measurement of noble gases in Antarctic ice cores

The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Polymers Based on Boron?

18.01.2018 | Life Sciences

Bioengineered soft microfibers improve T-cell production

18.01.2018 | Life Sciences

World’s oldest known oxygen oasis discovered

18.01.2018 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>