Ribosomes, the molecular machines in cells that make proteins, are constructed in a series of discrete steps to create both a large and a small subunit. Release of a key building block, eIF6, from the large 60S subunit allows assembly of the mature active ribosome. Alan Warren’s group, at the University of Cambridge, in collaboration with Rob Kay’s group in the LMB’s Cell Biology Division, and scientists from the University of Rennes and the Wellcome Trust Sanger Institute, have for the first time revealed the mechanism of release of this key assembly factor and how corruption of the process causes leukaemia, cancer of the blood.
Alan’s group, then based in the University Research Unit in the LMB building, used the latest developments in single particle cryo-EM at the LMB, to directly visualise the final maturation step of the 60S ribosomal subunit. Complementary genetic and biochemical studies in yeast were also undertaken. This work revealed the mechanism underlying the fundamental quality control step that licenses newly synthesised ribosomal subunits to enter active translation, a process conserved from archaea to human cells. It involves interrogation of the integrity of the peptide exit tunnel and all the active sites of the ribosome.
The groups also linked the pathogenesis of inherited and sporadic forms of leukaemia in a common pathway involved in maturation of the large ribosomal subunit. The study provides an explanation for how cellular processes go awry in an inherited disorder called Shwachman-Diamond syndrome, which is deficient in the protein SBDS, and one in 10 cases of T-cell acute lymphoblastic leukaemia in children. The study reveals a physical and functional link between the two proteins mutated in these disorders during ribosome maturation. It also raises the possibility that a single drug designed to target the underlying molecular fault could be developed to treat both inherited and sporadic forms of leukaemia.
This work was funded by the MRC, a FEBS Long term Fellowship, Bloodwise, the Wellcome Trust, Tesni Parry Trust, Ted’s Gang and the Cambridge NIHR Biomedical Research Centre.