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Alan Warren

Mechanisms of ribosome assembly

Ribosomes are the universally conserved macromolecular machines that decode the mRNA to make proteins. However, it remains unclear how these large ribonucleoprotein particles are assembled. Defects in the ribosome assembly process cause the 'ribosomopathies', a fascinating new group of human developmental disorders that perturb haematopoietic stem cell function and promote progression to bone marrow failure, myelodysplastic syndrome and acute leukaemia.

The key questions that underpin our current research are: what are the mechanisms of eukaryotic ribosome assembly; how is this process regulated and monitored; what are the cellular consequences of defective ribosome biogenesis; how do defects in this process cause human disease? My laboratory uses a highly interdisciplinary approach that combines genetics, biochemistry and high-resolution structural studies, with a particular focus on single-particle cryo-electron microscopy.

Warren lab
The Warren lab

Key papers

Zyryanova AF*, Weis F, Faille A, Alard AA, Crespillo-Casado A, Sekine Y, Harding HP, Allen F, Parts L, Fromont C, Fischer PM, Warren AJ* & Ron D.* Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science 359 (6383):1533-1536 (2018) *Corresponding authors

Weis F et al. Mechanism of eIF6 release from the nascent 60S ribosomal subunit. Nature Struct. Mol. Biol. doi:10.1038/nsmb.3112 (2015).

Ban N et al. A new system for naming ribosomal proteins. Curr. Opin. Struct. Biol. 24, 165–169 (2014).

Wong CC, Traynor D, Basse N, Kay RR & Warren AJ. Defective ribosome assembly in Shwachman-Diamond syndrome. Blood 118, 4305–4312 (2011).

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. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 25, 917–929 (2011).

Menne TM, Goyenechea B, Sánchez-Puig N, Wong CC, Tonkin LM, Ancliff P, Brost RL, Costanzo M, Boone C & Warren AJ. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genet. 39, 486–495 (2007).

Alan Warren

Alan J. Warren

Professor of Haematology

Department of Haematology

Contact: ajw1000@cam.ac.uk

 01223 748488

Plain English

The origins of inherited and acquired forms of blood cancer have recently been linked to defects in so-called 'housekeeping' processes in our cells, specifically in the assembly of the machines (called ribosomes) that make proteins. A major focus of our work is to understand in detail how ribosomes are put together from their component parts. To do this, we are learning about the three-dimensional shape of some of the key proteins involved and how these proteins work together in large complexes. As well as experiments in the test tube, we also use model organisms such as yeast and flies to test the effects of manipulating ribosome assembly in living organisms. The fundamental insights that we hope to obtain will potentially provide a deeper understanding of disease mechanisms.

Group members

Norberto Escudero · Alexandre Faille · Christine Hilcenko · Pekka Jaako · Vassileios Kargas · Maxim Rossman · Shengjiang Tan · Kyle Dent

 

 

Funding

Bloodwise

Medical Research Council

National Institutes of Health Research