A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation

Dis Model Mech. 2014 Aug;7(8):963-76. doi: 10.1242/dmm.014449. Epub 2014 May 15.


The central importance of translational control by post-translational modification has spurred major interest in regulatory pathways that control translation. One such pathway uniquely adds hypusine to eukaryotic initiation factor 5A (eIF5A), and thereby affects protein synthesis and, subsequently, cellular proliferation through an unknown mechanism. Using a novel conditional knockout mouse model and a Caenorhabditis elegans knockout model, we found an evolutionarily conserved role for the DOHH-mediated second step of hypusine synthesis in early embryonic development. At the cellular level, we observed reduced proliferation and induction of senescence in 3T3 Dohh-/- cells as well as reduced capability for malignant transformation. Furthermore, mass spectrometry showed that deletion of DOHH results in an unexpected complete loss of hypusine modification. Our results provide new biological insight into the physiological roles of the second step of the hypusination of eIF5A. Moreover, the conditional mouse model presented here provides a powerful tool for manipulating hypusine modification in a temporal and spatial manner, to analyse both how this unique modification normally functions in vivo as well as how it contributes to different pathological conditions.

Keywords: Cancer; Hypusine modification; Mouse models; Translational control.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3 Cells
  • Alleles
  • Animals
  • Caenorhabditis elegans
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology*
  • Cellular Senescence
  • Disease Models, Animal
  • Embryo Loss / metabolism
  • Embryo Loss / pathology
  • Embryonic Development*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Knockout Techniques
  • Hydroxylation
  • Lysine / analogs & derivatives*
  • Lysine / metabolism
  • Mice
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / metabolism
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Peptide Initiation Factors / metabolism
  • Phenotype
  • Protein Biosynthesis
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA-Binding Proteins / metabolism
  • ras Proteins / metabolism


  • Peptide Initiation Factors
  • Proto-Oncogene Proteins c-myc
  • RNA-Binding Proteins
  • eukaryotic translation initiation factor 5A
  • hypusine
  • Mixed Function Oxygenases
  • deoxyhypusine hydroxylase
  • Oxidoreductases Acting on CH-NH Group Donors
  • deoxyhypusine synthase
  • ras Proteins
  • Lysine