Recycler protein helps prevent genetic diseases

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Researchers identify protein recycling mechanism that helps protect from genetic

disorders

http://www.eurekalert.org/pub_releases/2009-04/embl-rph042809.php

Recycling is important not only on a global scale, but also at the cellular

level, since key molecules tend to be available in limited numbers. This means a

cell needs to have efficient recycling mechanisms. Researchers at the European

Molecular Biology Laboratory (EMBL) and Heidelberg University, Germany, have now

uncovered the first step in the recycling of a crucial molecular tag which

ensures the instructions encoded in our genes are correctly carried out. The

study, published this week in the journal Cell, sheds new light on a

proof-reading process that helps protect us from genetic diseases.

The translation of information from gene to protein in our cells is very

important, but also error-prone. As errors can lead to diseases, several control

mechanisms check for mistakes along the way. One such mechanism, called

nonsense-mediated decay (NMD), is based on a molecular tag that is attached to

messenger RNAs, an intermediate step in the translation from DNA to protein. The

tag, called exon-junction complex (EJC), tells the NMD machinery if an RNA is

faulty, potentially dangerous and should be degraded. Overall, a cell would need

to mark around 400,000 sites with EJCs, but it only has 10,000 copies of one of

the marker's components. This means EJCs must be broken down as soon as

possible, so that their components can be re-used.

Researchers in the groups of Matthias Hentze, associate director of EMBL, and

s Kulozik at the University Clinic Heidelberg discovered that a protein

called PYM is responsible for the disassembly and recycling of EJCs.

" Our results were very surprising, " says Niels Gehring, who carried out the

research. " Everybody had assumed that ribosomes, the large structures that carry

out protein assembly, simply iron out the EJCs as they pass. Now we see that

this is not quite right, because without PYM EJC disassembly is impaired. "

Although PYM can be found on its own in the cell, it tends to associate with

ribosomes. This explains why - and how - EJCs are removed when the ribosome goes

by, and could also ensure that they are not removed too early. If that happened,

NMD would be compromised, as the proofreading machinery would have no markers to

guide it. This in turn could have wider consequences, as NMD influences how

diseases such as thalassaemia, Duchenne's muscular dystrophy and cystic fibrosis

manifest themselves.

" The new insights fill an important gap in the basic understanding of a vital

cellular process, " says Hentze. " But they also have medical implications.

Ultimately we would like to find ways to modulate NMD pharmacologically to

influence the development and course of genetic diseases. "

The research was conducted in the joint Molecular Medicine Partnership Unit

(MMPU), a collaboration between EMBL and Heidelberg University. " The MMPU

bridges the gap between basic and clinical research. The constant

cross-fertilisation between biologists and medical scientists guides our studies

and often leads to discoveries that are applicable to medicine, " says Kulozik,

medical director and professor of pediatrics at Heidelberg University.