Targeting the stability of chromatin factors driving leukaemia


Project Summary

Inhibitors of several epigenetic regulators are potent in treating leukaemia. Our work has shown that the molecular chaperone Heat-shock protein 90 (Hsp90) binds chromatin and stabilises key chromatin factors including the Mixed Lineage Leukaemia protein. We hypothesise that destabilising epigenetic regulators by inhibiting Hsp90 will be beneficial in controlling leukaemia. We shall identify the oncogenic network of proteins stabilised by Hsp90 at chromatin and define the genome-wide location of Hsp90 binding in leukaemic cells. The outcome of the project will pave a way for new concepts for therapeutic intervention.

Selected project-relevant publications

  • Aprile-Garcia F., Tomar P., Hummel B., Khavaran A. and Sawarkar R. (2019) Nascent-protein ubiquitination is required for heat shock-induced gene downregulation in human cells. Nat Struct Mol Biol 26, 137-146.
  • Vincenz-Donnelly L., Holthusen H., Korner R., Hansen E.C., Presto J., Johansson J., Sawarkar R., Hartl F.U. and Hipp M.S. (2018) High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins. EMBO J 37, 337-350.
  • Hummel B., Hansen E.C., Yoveva A., Aprile-Garcia F., Hussong R. and Sawarkar R. (2017) The evolutionary capacitor HSP90 buffers the regulatory effects of mammalian endogenous retroviruses. Nat Struct Mol Biol 24, 234-242.
  • Irmak D., Fatima A., Gutierrez-Garcia R., Rinschen M.M., Wagle P., Altmuller J., Arrigoni L., Hummel B., Klein C., Frese C.K., Sawarkar R., Rada-Iglesias A. and Vilchez D. (2018) Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations. Hum Mol Genet 27, 4117-4134.
  • Friedensohn S. and Sawarkar R. (2014) Cis-regulatory variation: significance in biomedicine and evolution. Cell Tissue Res 356, 495-505.
  • Sawarkar R. and Paro R. (2013) Hsp90@chromatin.nucleus: an emerging hub of a networker. Trends Cell Biol 23, 193-201.
  • Sawarkar R., Sievers C. and Paro R. (2012) Hsp90 globally targets paused RNA polymerase to regulate gene expression in response to environmental stimuli. Cell 149, 807-818.
  • Sawarkar R. and Paro R. (2010) Interpretation of developmental signaling at chromatin: the Polycomb perspective. Dev Cell 19, 651-661.
  • Sawarkar R. and Paro R. (2010) Heat shock protein 90: a capacitor or a mutator? J Biosci 35, 163-165.
  • Sawarkar R., Visweswariah S.S., Nellen W. and Nanjundiah V. (2009) Histone deacetylases regulate multicellular development in the social amoeba Dictyostelium discoideum. J Mol Biol 391, 833-848.
  • Sawarkar R., Roy N., Rao S., Raman S., Venketesh S., Suguna K. and Tatu U. (2008) Heat shock protein 90 regulates development in Dictyostelium discoideum. J Mol Biol 383, 24-35.