Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study provides insight into cellular defenses against genetic mutation

26.10.2005


Nature’s finesse revealed in quality surveillance system



With their latest discovery, researchers have significantly advanced the understanding of how human cells protect themselves from constant and potentially destructive changes in gene expression. According to an article published in this month’s Nature Structural & Molecular Biology, the research is important because the protection itself can contribute to disease, and the ability to side-step it may lead to new treatments for hundreds of genetic disorders.

The blueprint for the human body is encoded in genes, many of which hold the information necessary for the building of one or more proteins. Gene expression is the process by which information stored in genes is coverted into proteins that make up the body’s structures and carry out its functions. While genetic instructions are stored in chains of deoxyribonucleic acids (DNA), they are put into practice by ribonucleic acids (RNA). Messenger RNA (mRNA), a modified copy of DNA, is transported to cellular factories called ribosomes that receive instructions for building proteins by "reading" mRNA templates.


Over time, genes evolve to show changes in their makeup. Some changes, or mutations, have no impact, some provide advantages making organisms more likely to survive, and others cause disease. One frequently occurring, damaging class of mutation is the inclusion of premature "stop reading" signals (stop codons) within mRNAs. Called "frameshift" or "nonsense" mutations, they order the genetic process to stop reading part way through the instructions, resulting in the building of incomplete proteins. Affected mRNAs create shortened, disabled proteins that can sabotage natural processes by competing for spots usually held by their full-length counterparts, or by simply not working.

In recent years, researchers at the University of Rochester Medical Center have revealed the existence of a natural surveillance system that determines which mRNAs pass muster as legitimate templates, and that sees to the destruction of the rest. They also found that the screening process, called nonsense-mediated mRNA decay (NMD), can nearly eliminate the supply of an mRNA template for an essential protein because the mRNA has acquired a nonsense codon.

"Our study is important because we have determined for the first time that the mRNA-binding protein CBP80 tells the NMD system which mRNAs to review for nonsense codons," according to Lynne E. Maquat, Ph.D., professor of Biochemistry and Biophysics at the Medical Center, and senior author of the Nature piece together with post-doctoral associate Nao Hosoda, Ph.D. "That is critically significant because, knowing the structure and role of CBP80, we can now seek to develop drug-based gene therapies that interfere with it in cases where NMD contributes to disease-causing protein shortages." Researchers may be able to convert mRNA quality control from NMD over to a more flexible system that "overlooks" flaws, and provides more templates for building functional proteins.

Genetic Decision Maker

For two decades, researchers have made intuitive leaps in the understanding how NMD works with translation, the second phase of gene expression where RNAs direct the building of proteins. From studying genetic diseases, Maquat theorized four years ago that there must be two types of translation. An early "pioneer" round checks all new mRNAs for errors, and initiates NMD when errors are detected. A second "steady-state" round translation then directs the mass production of normal proteins based on "NMD-approved" mRNAs. Recently, Maquat’s team has worked to identify the roles of proteins involved in NMD, the focus of the Nature paper.

During translation, mRNA chains are read in one direction due to the nature of their building blocks, called nucleotides, starting with the 5-prime end, and ending with the 3-prime end. As mRNA chains are synthesized, a 7-methylguanosine cap is attached to the 5-prime end and a tail of repeating adenosine molecules to the 3-prime end. The cap and the tail protect the mRNA from enzymes that would otherwise destroy it from both ends.

Along with its protective role, the 5-prime cap is designed to bind to a complex of two linked cap-binding proteins (CBPs), CBP80 and CBP20. The cap-binding complex is part of the larger pioneer translation initiation complex, which enables mRNAs to be read by ribosomes during quality control review. Previous studies in the Maquat lab revealed two vital facts about cap-binding proteins. First, any mRNA with a CBP80 attached to its 5-prime cap can be translated by ribosomes. Secondly, mRNAs linked to CBP80 are targeted for NMD when a ribosome finds an early stop codon. Most recently, the Nature paper demonstrated for the first time that CBP80 works by activating a protein factor known to drive NMD called human up-frameshift (hUpf) protein 1.

A Matter of Spacing

Immature mRNA is made of both "must-read" pieces of RNA called exons that code for the building of proteins, and pieces called introns that do not code for proteins. For mRNA to mature, it must be cut and pasted by cellular machines that re-assemble end to end only exons in the final template for protein construction. In recent years, Maquat’s team has confirmed that complexes that identify early nonsense codons form at exon-exon junctions the places where each "must read" section is joined to the next in the mature chain.

What Maquat and colleagues are learning is that much of the regulatory action of NMD depends on the physical spacing of molecules in the RNA chain. If a stop reading signal occurs too far ahead of the final exon in the chain, as marked by an exon-exon junction complex (EJC), the cell concludes that the stop codon has mistakenly fallen in the middle of a set of instructions. Specifically, Medical Center researchers now believe a stop codon is labeled premature when it occurs more than 55 nucleotides upstream (toward the 5-prime end) of an exon-exon junction.

If these spatial requirements are met, CBP80 interacts with human up-frameshift proteins, factors that come together at exon-exon junction complexes to drive NMD review. The three up-frameshift proteins work together to trigger decay once an early nonsense codon is detected, most likely by recruiting enzymes that remove the tail and cap from suspect mRNAs and digest their chains. If nonsense codons are not detected, CBP80 and its partner CBP20 are replaced by another cap-binding protein that renders mRNA immune to further notice by NMD.

"NMD is an elegant process that offers a number of targets for future medical therapies," Maquat said. "Beyond its role in screening out faulty mRNAs through immediate decay, we have also learned that the NMD factor Upf1 is part of a related process that regulates the expression of many normal genes by controlling the timeframe in which their encoded mRNAs decay. Evolution often borrows a useful mechanism from one process and puts it to work in another."

Greg Williams | EurekAlert!
Further information:
http://www.urmc.rochester.edu

More articles from Studies and Analyses:

nachricht Europe’s Demographic Future. Where the Regions Are Heading after a Decade of Crises
10.08.2017 | Berlin-Institut für Bevölkerung und Entwicklung

nachricht Scientists reveal source of human heartbeat in 3-D
07.08.2017 | University of Manchester

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>