1. Academic Validation
  2. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

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.
Katherine A Donovan 1 2 Jian An 1 2 Radosław P Nowak 1 2 Jingting C Yuan 1 Emma C Fink 3 4 Bethany C Berry 1 Benjamin L Ebert 3 4 Eric S Fischer 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
  • 3 Division of Hematology, Brigham and Women's Hospital, Boston, United States.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
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.

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