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| Heidelberg,
Thursday 6 October 2005 |
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| Defusing dangerous mutations |
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| Matthias
Hentze and Andreas Kulozik |
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Press
Release 6 October 2005 [PDF]
Scientists discover a new way by which cells control genetic errors
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.
Andreas 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."
Gehring and his colleagues have found that
at least two EJC complexes can be built on RNAs
which determines how the protein UPF1 is recruited
to the complex. [JPEG]
Source article
Exon-junction complex components specify distinct
routes of nonsense-mediated mRNA decay with differential
co-factor requirements
N.H. Gehring, J.B. Kunz, G. Neu-Yilik,
S. Breit, M.H. Viegas, M.W. Hentze and A.E. Kulozik
Molecular Cell, 7 October 2005
Press contact
Sarah Sherwood
EMBL Information Officer, European Molecular Biology Laboratory,
Meyerhofstrasse 1, 69117 Heidelberg, Germany
Tel: +49 [0] 6221 387125
E-mail: sarah.sherwood@embl.de |
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