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Principal Investigators

Department of Haematology

School of Clinical Medicine

Professor Alan J Warren

Professor of Haematology

PI Photo

Email: ajw1000@cam.ac.uk

Home page: https://www.cimr.cam.ac.uk/staff/professor-alan-j-warren-fmedsci

Description of research

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. Our research on the mechanisms of ribosome assembly centres around the ribosomopathies with Shwachman-Diamond syndrome currently a key focus for us.

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.

Research focus

Keywords: Ribosome biogenesis, Stem cells, Genetics, Structural biology, RNA processing

Clinical conditions: Myelodysplastic syndromes, Leukaemia, Inherited bone marrow failure syndromes, Shwachman-Diamond syndrome, Poikiloderma with neutropenia

Methodologies: Model organisms (Drosophila, yeast, Dictyostelium), mammalian genetics, confocal microscopy, X-ray crystallography, NMR spectroscopy, Cryo-EM, protein expression and purification, molecular biology, biochemistry

Cambridge collaborators

  • Mark Bycroft (MRC Laboratory of Molecular Biology)
  • Peter Campbell (Wellcome Sanger Institute)
  • Stefan Freund (MRC Laboratory of Molecular Biology)
  • Sjors Scheres (MRC Laboratory of Molecular Biology)

Other collaborators

  • Alexey Amunts (Science for Life Laboratory, Stockholm, Sweden)
  • Helmut Bergler (University of Graz, Austria)
  • Charlie Boone (University of Toronto, Canada)
  • Cornelis Calkhoven (University of Groningen, The Netherlands)
  • Jesus de la Cruz (University of Seville, Spain)
  • Kim de Keersmaecker (KU Leuven, Belgium)
  • David Kent (University of York, UK)

Funders

Key Publications

Machado HE*, Øbro NF*, Williams N*, Tan S*, Boukerrou AZ, Davies M, Belmonte M, Mitchell E, Baxter EJ, Mende N, Clay A, Ancliff P, Köglmeier J, Killick SB, Kulasekararaj A, Meyer S, Laurenti E, Campbell PJ, Kent DG#, Nangalia J#, Warren AJ#. Convergent somatic evolution commences in utero in a germline ribosomopathy. Nat Commun. 2023 Aug 22;14(1):5092. doi: 10.1038/s41467-023-40896-5. PMID: 37608017 *Contributed equally. #Corresponding authors.

Fioredda F, Skokowa J, Tamary H, Spanoudakis M, Farruggia P, Almeida A, Guardo D, Höglund P, Newburger PE, Palmblad J, Touw IP, Zeidler C, Warren AJ, Dale DC, Welte K, Dufour C, Papadaki HA. The European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children: A Consensus Between the European Hematology Association and the EuNet-INNOCHRON COST Action. Hemasphere. 2023 Mar 30;7(4):e872. doi: 10.1097/HS9.0000000000000872. PMID: 37008163

Pellegrino S, Dent KC, Spikes T, Warren AJ. Cryo-EM reconstruction of the human 40S ribosomal subunit at 2.15 Å resolution. Nucleic Acids Res. 2023 Mar 23:gkad194. doi: 10.1093/nar/gkad194. PMID: 36951107

Faille A, Warren AJ. Teaching old drugs new tricks. Elife. 2022 Dec 8;11:e84702. doi: 10.7554/eLife.84702. PMID: 36480270

Gordon J, Chapus FL, Viverette EG, Williams JG, Deterding LJ, Krahn JM, Borgnia MJ, Rodriguez J, Warren AJ, Stanley RE. Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold. Nat Commun. 2022 Nov 9;13(1):6783. doi: 10.1038/s41467-022-34610-0. PMID: 36351913

Prattes M, Grishkovskaya I, Hodirnau VV, Hetzmannseder C, Zisser G, Sailer C, Kargas V, Loibl M, Gerhalter M, Kofler L, Warren AJ, Stengel F, Haselbach D, Bergler H. Visualizing maturation factor extraction from the nascent ribosome by the AAA-ATPase Drg1. Nat Struct Mol Biol. 2022 Sep;29(9):942-953. doi: 10.1038/s41594-022-00832-5. Epub 2022 Sep 12. PMID: 36097293

Cantilena S, Gasparoli L, Pal D, Heidenreich O, Klusmann JH, Martens JHA, Faille A, Warren AJ, Karsa M, Pandher R, Somers K, Williams O, de Boer J. Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias. Clin Transl Med. 2022 Jun;12(6):e933. doi: 10.1002/ctm2.933. PMID: 35730653

Jaako P, Faille A, Tan S, Wong CC, Escudero-Urquijo N, Castro-Hartmann P, Wright P, Hilcenko C, Adams DJ, Warren AJ. eIF6 rebinding dynamically couples ribosome maturation and translation. Nat Commun. 2022 Mar 23;13(1):1562. doi: 10.1038/s41467-022-29214-7. PMID: 35322020

Rebelo-Guiomar P, Pellegrino S, Dent KC, Sas-Chen A, Miller-Fleming L, Garone C, Van Haute L, Rogan JF, Dinan A, Firth AE, Andrews B, Whitworth AJ, Schwartz S, Warren AJ, Minczuk M. A late-stage assembly checkpoint of the human mitochondrial ribosome large subunit. Nat Commun. 2022 Feb 17;13(1):929. doi: 10.1038/s41467-022-28503-5. PMID: 35177605.

Warren AJ. Road to RIO-kinase 2 for AML therapy. Blood. 2022 Jan 13;139(2):156-157. doi: 10.1182/blood.2021013618. PMID: 35024808.

Shoo A, Swai P, Kindole C, Ngailo E, Godfrey E, Massawe E, Warren AJ, Luzzatto L. Severe congenital neutropenia with elastase, neutrophil expressed (ELANE) gene mutation in a Tanzanian child. Br J Haematol. 2021 Nov 1. doi: 10.1111/bjh.17924. PMID: 34725814.

Tan S, Kermasson L, Hilcenko C, Kargas V, Traynor D, Boukerrou AZ, Escudero-Urquijo N, Faille A, Bertrand A, Rossmann M, Goyenechea B, Jin L, Moreil J, Alibeu O, Beaupain B, Bôle-Feysot C, Fumagalli S, Kaltenbach S, Martignoles JA, Masson C, Nitschké P, Parisot M, Pouliet A, Radford-Weiss I, Tores F, de Villartay JP, Zarhrate M, Koh AL, Phua KB, Reversade B, Bond PJ, Bellanné-Chantelot C, Callebaut I, Delhommeau F, Donadieu J, Warren AJ, Revy P. Somatic genetic rescue of a germline ribosome assembly defect. Nat Commun. 2021 Aug 19;12(1):5044. doi: 10.1038/s41467-021-24999-5. PMID: 34413298

Lv K, Gong C, Antony C, Han X, Ren JG, Donaghy R, Cheng Y, Pellegrino S, Warren AJ, Paralkar VR, Tong W. HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis.  Cell Stem Cell. 2021 Mar 4:S1934-5909(21)00058-8. doi: 10.1016/j.stem.2021.02.008. PMID: 33711283

Warren AJ. DNA-repair enzyme turns to translation. Nature. 2020 Mar;579(7798):198-199. doi: 10.1038/d41586-020-00424-7. PMID: 32152600

Lakshminarayan R, Phillips BP, Binnian IL, Gomez-Navarro N, Escudero-Urquijo N, Warren AJ, Miller EA. Pre-emptive Quality Control of a Misfolded Membrane Protein by Ribosome-Driven Effects. Curr Biol. 2020 Mar 9;30(5):854-864.e5. doi: 10.1016/j.cub.2019.12.060. PMID: 31956032

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. doi: 10.1182/blood.2018893404. PMID: 31151987

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. doi: 10.7554/eLife.44904. PMID: 31115337 *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* and Ron D*. Binding of the integrated stress response inhibitor ISRIB reveals a regulatory site in the nucleotide exchange factor, eIF2B. Science. 2018 Mar 30;359 (6383):1533-1536. doi: 10.1126/science.aar5129. *Joint corresponding authors. PMID: 29599245

Warren AJ. Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome. Adv Biol Regul.2018 Jan; 67:109-127. doi: 10.1016/j.jbior.2017.09.002. PMID: 28942353

In K, Zaini MA, Müller C, Warren AJ, von Lindern M and Calkhoven CF. Shwachman-Bodian-Diamond Syndrome (SBDS) protein deficiency impairs translation re-initiation from C/EBPα and C/EBPβ mRNAs. Nucleic Acids Res. 2016 May 19;44(9):4134-46. doi: 10.1093/nar/gkw005. PMID: 26762974

Weis F, Giudice E, Churcher M, Jin L, Hilcenko C, Wong CC, Traynor D, Kay RR, Warren AJ. Mechanism of eIF6 release from the nascent 60S ribosomal subunit. Nat Struct Mol Biol. 2015 Nov;22(11):914-9. doi: 10.1038/nsmb.3112. PMID: 26479198.

Ban N, Beckmann R, Cate JH, Dinman JD, Dragon F, Ellis SR, Lafontaine DL, Lindahl L, Liljas A, Lipton JM, McAlear MA, Moore PB, Noller HF, Ortega J, Panse VG, Ramakrishnan V, Spahn CM, Steitz TA, Tchorzewski M, Tollervey D, Warren AJ, Williamson JR, Wilson D, Yonath A, Yusupov M. A new system for naming ribosomal proteins. Curr Opin Struct Biol. 2014 Feb; 24:165-9. doi: 10.1016/j.sbi.2014.01.002. PMID: 24524803

Hilcenko C, Simpson PJ, Finch AJ, Bowler FR, Churcher MJ, Jin L, Packman LC, Shlien A, Campbell P, Kirwan M, Dokal I, Warren AJ. Aberrant 3’ oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia. Blood. 2013 Feb 7;121(6):1028-38. doi: 10.1182/blood-2012-10-461491. Epub 2012 Nov 27. PMID: 23190533

Wong CC, Traynor D, Basse N, Kay RR, Warren AJ. Defective ribosome assembly in Shwachman-Diamond syndrome. Plenary Paper, Blood. 2011 Oct 20;118(16):4305-12. doi: 10.1182/blood-2011-06-353938. Epub 2011 Jul 29. PMID: 21803848

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 and Development (2011) 25: 917-929. PMID: 21536732

Barlow JL, Drynan LF, Hewett DR, Holmes LR, Lorenzo-Abalde S, Lane AL, Jolin HE, Pannell R, Middleton AJ, Wong SH, Warren AJ, Wainscoat JS, Boultwood J, McKenzie AN. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome. Nat Med. (2010) Jan; 16(1): 59-66. Epub 2009 Nov 22. PMID: 19966810.

Menne TM, Goyenechea B, Sánchez-Puig N, Wong CC, Tonkin LM, Ancliff P, Brost RL, Costanzo M, Boone C and Warren AJ. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genetics (2007) 39: 486-95. PMID:17353896

Allen MD, Grummitt CG, Hilcenko, C, Young Min S, Tonkin LM, Johnson CM, Freund S, Bycroft SM, Warren AJ. Solution structure of the nonmethyl-CpG-binding CXXC domain from the leukaemia-associated MLL histone methyltransferase. EMBO J. 2006, 25: 4503-12.

Bravo J, Li Z, Speck NA, Warren AJ. The leukemia-associated AML1 (Runx1)-CBFb complex functions as a DNA-induced molecular clamp. Nature Struct. Biol. 2001 8: 371-8.

Warren AJ, Bravo J, Williams RL, Rabbitts TH. Structural basis for the heterodimeric interaction between the acute leukaemia-associated transcription factors AML1 and CBFb. EMBO J. 2000 19: 3004-15.

Warren AJ, Colledge WH, Carlton MB, Evans MJ, Smith AJ, Rabbitts TH. The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell 1994 78: 45-57.

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