Studying the origins of leukemia by observing ribosome assembly

With people from Alan Warren’s group, Rob Kay’s MRC Laboratory of Molecular Biology, and the Wellcome Trust Sanger Institute (all of Cambridge University), IGDR lecturer/researcher Emmanuel Giudice worked on a study which showed how a change in the last steps of ribosome maturation can cause certain leukemias. Publication in the journal Nature Structural & Molecular Biology.

Ribosomes ?

Ribosomes are the molecular machines which use our genetic code to construct proteins, the molecules which are the basis for all cell functions. Ribosomal assembly is a complex process which involves more than 300 factors whose functions are still mostly unknown. The smallest disruption of this process can lead to disastrous consequences for the organism. Problems with the ribosomal assembly process are implicated in several rare genetic diseases such as Shwachman-Diamond syndrome, and are observed in a large number of cancers, notably in certain leukemias.

Ribosomes are made of two subunits of different sizes: the small 40S, and the large 60S. A key step in ribosomal assembly is the joining of these two subunits. Since each is created separately, it is essential to ensure that they are properly constructed before they come together. To do this, during construction the protein eIF6 fixes to the large subunit’s surface and stops the small one from joining to it. eIF6 is freed by the joint action of two other proteins, EFL1 and SBDS (the latter known to be mutated in Shwachman-Diamond syndrome).

Molecular modeling

In this study, the researchers used the latest cryo-electron microscopy and molecular modelling techniques. Even though the structures measure only some thousand millionths of meters, these methods allowed for the direct visualization of the last three maturation steps of the 60S ribosomal subunits.

These results explain how:
1. the protein SBDS protects the large ribosomal subunit during assembly;
2. the protein eIF6 is kicked out once the large subunit matures;
3. certain mutations in either the SBDS protein or in the large sub-unit lead to tumour formation.

For more info

>> Abstract and references from the article "Mechanism of eIF6 release from the nascent 60S ribosomal subunit" published in the journal Nature Structural & Molecular Biology

The article was published on the University of Rennes 1’s web site on October 23, 2015.

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