Scientists discover a new way by which cells control genetic errors

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Scientists discover a new way by which cells control genetic errors

http://www.medicalnewstoday.com/medicalnews.php?newsid=31688

07 Oct 2005

Mutations in genes are the basis of evolution, so we owe our

existence to them. Most mutations are harmful, however, because they

cause cells to build defective proteins. So cells have evolved

quality control mechanisms that recognize and counteract genetic

mistakes. Now 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. The

work appears in the October issue of Molecular Cell.

Both healthy and damaged proteins begin as instructions in genes.

Cells read this information and create an RNA molecule, a template

that will be used to create proteins. RNAs usually contain extra bits

of code that have to be cut out before they can be used. During this

cut-and-paste operation, cells attach a group of molecules called the

exon junction complex (EJC) to the RNA. An RNA made from a mutant

gene usually has an EJC in the wrong position, which activates NMD

and destroys the RNA before it can be used to make flawed proteins.

s Kulozik and Matthias Hentze, who jointly run the MMPU, have

now discovered that the EJC can be put together from different

components, and this influences how the cell recognizes and deals

with defects.

" Previously it was believed that animal cells had one standard type

of EJC 'machine' which alerted cells to errors and activated NMD, "

Hentze says. " In the current study we removed one of the components

of this machine, a protein called UPF2, and watched how the cell

responded. We discovered that there are at least two kinds of NMD:

one requires UPF2 and the other does not. "

The presence or absence of UPF2 changes the composition of the EJC,

giving it different surfaces for other molecules to grip onto. This

affects the way that another component, called UPF1, fits onto the

machine. UPF1 is directly responsible for calling up the NMD

machinery. The study shows that UPF1 can be mounted on both EJC

types; the final effect is the same - to efficiently break down

faulty RNAs.

Niels Gehring, who headed the project, did extensive studies with

colleagues in the MMPU to understand exactly how the pieces of the

EJC fit together. " By slightly altering some of the components, we

could change the way they snapped onto the RNA and each other, "

Gehring says. " This gave us a very detailed look at the step-wise way

in which the EJC can be assembled in two different ways, and what

that means for NMD. "

Understanding this process should shed new light on some genetic

diseases, says Kulozik, a clinical researcher at the University of

Heidelberg. " Some mutations manage to escape NMD and go on to cause

disease. Until now we've thought that there is one road leading to

NMD; discovering a second one will obviously give us a much clearer

look at how cells deal with errors - or fail to do so. "

" The goal of EMBL and the University in setting up the MMPU was to

create a real marriage between basic research and the clinic to help

us understand medically-relevant processes, " Hentze says. " The

current study is a perfect example, because it takes us all the way

from the details of single molecules to an important disease

mechanism. "

European Molecular Biology Laboratory

http://www.embl.org