Wong CC, Traynor D, Basse N, Kay RR, Warren AJ. (2011)
Defective ribosome assembly in Shwachman-Diamond syndrome.
Blood. Plenary Paper. Published online before print July 29, 2011, doi: 10.1182/blood-2011-06-353938.
Finch AJ, Hilcenko C, Basse N, Drynan LF, Goyenechea B, Menne TF, González Fernández Á, Simpson P, D’Santos CS, Arends MJ, Donadieu J, Bellanné-Chantelot C, Costanzo M, Boone C, McKenzie AN, Freund SM, Warren AJ. (2011)
Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.
Genes and Development 25:917-929.
Menne, T.M., Goyenechea, B., Sánchez-Puig, N., Wong, C.C., Tonkin, L.M., Ancliff, P., Brost, R.L., Costanzo, M., Boone, C. & Warren, A.J. (2007)
The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast.
Nature Genetics 39, 486-95.
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Group Members
- Mark Churcher
- Christine Hilcenko
- Chi Wong
- Shengjiang Tan
- Andrew Finch
- Lily Jin (Tan)
- Felix Weis
- Valentina Andre
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The synthesis of functional ribosomes is a critical process for all eukaryotic cells, but the underlying molecular mechanisms remain poorly understood. An exciting body of recent data indicates that mutations in genes with critical functions in ribosome biogenesis can cause bone marrow failure and leukaemia.
Our goal is to elucidate the molecular mechanisms underlying eukaryotic ribosome biogenesis. Our focus is the SBDS gene that is mutated in Shwachman-Diamond syndrome, a human developmental disorder associated with significant leukaemia predisposition.
We have determined the crystal structure of an archaeal SBDS homologue and using an automated yeast genetics platform, we have discovered a critical role for SBDS in maturation of the large ribosomal subunit. However, the precise function of SBDS remains unknown.
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 Suppressor mutations in Tif6 can bypass SBDS deletion in yeast.
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| We aim to elucidate the molecular mechanism of SBDS function in 60S ribosomal subunit maturation and to understand how perturbation of this function results in defective haematopoiesis and leukaemia. As the key components of the ribosome assembly pathway are highly conserved in all eukaryotic cells, this allows us to exploit genetic, cellular and molecular approaches in a variety of model organisms to obtain mechanistic insights and to identify novel components of the pathway. Using the complementary tools of X-ray crystallography and NMR spectroscopy, we aim to build a detailed structural and functional model of 60S ribosomal subunit maturation. We are also developing tools to study the function of ribosome biogenesis factors in mammalian cells.
Our goal is to exploit novel mechanistic insights for the design of cancer therapeutics targeting components of the translational apparatus.
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Group Leaders 
