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.
- The Warren lab
Key papers
Tan S, Kermasson L, Hoslin A, Jaako P, Faille A, Acevedo-Arozena A, Lengline E, Ranta D, Poirée M, Fenneteau O, Ducou le Pointe H, Fumagalli S, Beaupain B, Nitschké P, Bôle-Feysot C, de Villartay JP, Bellanné-Chantelot C, Donadieu J, Kannengiesser C, Warren AJ, Revy P. EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome. Blood. 2019 May 31. pii: blood.2018893404 (2019)
Kargas V*, Castro-Hartmann P*, Escudero-Urquijo N, Dent K, Hilcenko C, Sailer C, Zisser G, Marques-Carvalho MJ, Pellegrino S, Wawiórka L, Freund SM, Wagstaff JL, Andreeva A, Faille A, Chen E, Stengel F, Bergler H, Warren AJ. Mechanism of completion of peptidyltransferase centre assembly in eukaryotes. Elife. 2019 May 22;8. pii: e44904. (2019) *Joint first authors
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).
