Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

Elife. 2018 Aug 1;7:e38430. doi: 10.7554/eLife.38430.

Abstract

In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C2H2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.

Keywords: biochemistry; chemical biology; developmental biology; human; teratogenicity; transcription factors; ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / metabolism
  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • CYS2-HIS2 Zinc Fingers
  • Duane Retraction Syndrome / metabolism*
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism
  • HEK293 Cells
  • Heart Defects, Congenital / metabolism
  • Heart Septal Defects, Atrial / metabolism
  • Humans
  • Lower Extremity Deformities, Congenital / metabolism
  • Peptide Hydrolases / metabolism
  • Phenotype
  • Protein Binding / drug effects
  • Proteolysis / drug effects*
  • Reproducibility of Results
  • Species Specificity
  • Substrate Specificity
  • Teratogens / toxicity
  • Thalidomide / chemistry
  • Thalidomide / pharmacology*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • Upper Extremity Deformities, Congenital / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CRBN protein, human
  • SALL4 protein, human
  • Teratogens
  • Transcription Factors
  • Thalidomide
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • CRL4 protein, human

Supplementary concepts

  • Holt-Oram syndrome