Mechanisms of eukaryotic ribosome assembly
We are interested in the molecular mechanisms of eukaryotic ribosome assembly, an essential, highly conserved process that is tightly coupled to cell growth and proliferation. This fundamental process involves more than 200 assembly factors whose functions still remain poorly understood. Furthermore, mutations in multiple components of the ribosome assembly pathway characterise the 'ribosomopathies', an emerging new class of human developmental and cancer predisposition disorders. In particular, we discovered that the SBDS protein that is deficient in the leukaemia predisposition disorder Shwachman-Diamond syndrome (SDS) is critical for a late cytoplasmic step in maturation of the large ribosomal subunit.
Key questions that underpin our current research are: how are eukaryotic ribosomes assembled; 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 using state-of-the-art NMR spectroscopy, X-ray crystallography and single-particle cryo-electron microscopy.
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., Beckmann, R., Cate, J. H., Dinman, J. D., Dragon, F., Ellis, S. R., Lafontaine, D. L., Lindahl, L., Liljas, A., Lipton, J. M., McAlear, M. A., Moore, P. B., Noller, H. F., Ortega, J., Panse, V. G., Ramakrishnan, V., Spahn, C. M., Steitz, T. A., Tchorzewski, M., Tollervey, D., Warren, A. J., Williamson, J. R., Wilson, D., Yonath, A. and Yusupov, M. A new system for naming ribosomal proteins. Curr. Opin. Struct. Biol. 24, 165–169 (2014)
Wong, C. C., Traynor, D., Basse, N., Kay, R. R. and Warren, A. J. Defective ribosome assembly in Shwachman-Diamond syndrome. Blood 118, 4305–4312 (2011).
Finch, A. J., Hilcenko, C., Basse, N., Drynan, L. F., Goyenechea, B., Menne, T. F., González Fernández, Á., Simpson, P., D’Santos, C. S., Arends, M. J., Donadieu, J., Bellanné-Chantelot, C., Costanzo, M., Boone, C., McKenzie, A. N., Freund, S. M. and Warren, A. J. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 25, 917–929 (2011).
Menne, T. M., Goyenechea, B., Sánchez-Puig, N., Wong, C. C., Tonkin, L. M., Ancliff, P., Brost, R. L., Costanzo, M., Boone, C. and Warren, A. J. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genet. 39, 486–495 (2007).