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Defusing Dangerous Mutations: Scientists Discover A New Way By Which Cells Control Genetic Errors

Date:
October 10, 2005
Source:
European Molecular Biology Laboratory
Summary:
Scientists of the Molecular Medicine Partnership Unit (MMPU), a laboratory operated jointly by the European Molecular Biology Laboratory (EMBL) and the University of Heidelberg, have discovered new features of a key quality-control mechanism in our cells. These insights into Nonsense-Mediated Decay (NMD), a process by which cells destroy potentially harmful molecules, promise to clarify our understanding of how some mutations lead to disease.

Gehring and his colleagues have found that at least two EJC complexes can be built on RNAs [left and right], which determines how the protein UPF1 is recruited to the complex. Distinct RNAs might attract different EJCs, which influences how NMD deals with defective RNA molecules.
Credit: Petra Riedinger, OIPA, EMBL Heidelberg

Both healthy anddamaged proteins begin as instructions in genes. Cells read thisinformation and create an RNA molecule, a template that will be used tocreate proteins. RNAs usually contain extra bits of code that have tobe cut out before they can be used. During this cut-and-pasteoperation, cells attach a group of molecules called the exon junctioncomplex (EJC) to the RNA. An RNA made from a mutant gene usually has anEJC in the wrong position, which activates NMD and destroys the RNAbefore it can be used to make flawed proteins.

Andreas Kulozikand Matthias Hentze, who jointly run the MMPU, have now discovered thatthe EJC can be put together from different components, and thisinfluences how the cell recognizes and deals with defects.

"Previouslyit was believed that animal cells had one standard type of EJC'machine' which alerted cells to errors and activated NMD," Hentzesays. "In the current study we removed one of the components of thismachine, a protein called UPF2, and watched how the cell responded. Wediscovered that there are at least two kinds of NMD: one requires UPF2and the other does not."

The presence or absence of UPF2 changesthe composition of the EJC, giving it different surfaces for othermolecules to grip onto. This affects the way that another component,called UPF1, fits onto the machine. UPF1 is directly responsible forcalling up the NMD machinery. The study shows that UPF1 can be mountedon both EJC types; the final effect is the same – to efficiently breakdown faulty RNAs.

Niels Gehring, who headed the project, didextensive studies with colleagues in the MMPU to understand exactly howthe pieces of the EJC fit together. "By slightly altering some of thecomponents, we could change the way they snapped onto the RNA and eachother," Gehring says. "This gave us a very detailed look at thestep-wise way in which the EJC can be assembled in two different ways,and what that means for NMD."

Understanding this process shouldshed new light on some genetic diseases, says Kulozik, a clinicalresearcher at the University of Heidelberg. "Some mutations manage toescape NMD and go on to cause disease. Until now we've thought thatthere is one road leading to NMD; discovering a second one willobviously give us a much clearer look at how cells deal with errors –or fail to do so."

"The goal of EMBL and the University insetting up the MMPU was to create a real marriage between basicresearch and the clinic to help us understand medically-relevantprocesses," Hentze says. "The current study is a perfect example,because it takes us all the way from the details of single molecules toan important disease mechanism."


Story Source:

The above story is based on materials provided by European Molecular Biology Laboratory. Note: Materials may be edited for content and length.


Cite This Page:

European Molecular Biology Laboratory. "Defusing Dangerous Mutations: Scientists Discover A New Way By Which Cells Control Genetic Errors." ScienceDaily. ScienceDaily, 10 October 2005. <www.sciencedaily.com/releases/2005/10/051007100518.htm>.
European Molecular Biology Laboratory. (2005, October 10). Defusing Dangerous Mutations: Scientists Discover A New Way By Which Cells Control Genetic Errors. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2005/10/051007100518.htm
European Molecular Biology Laboratory. "Defusing Dangerous Mutations: Scientists Discover A New Way By Which Cells Control Genetic Errors." ScienceDaily. www.sciencedaily.com/releases/2005/10/051007100518.htm (accessed July 31, 2014).

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