Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome
- Dana-Farber Cancer Institute, United States
- Brigham and Women's Hospital, United States
Abstract
Frequently used to treat morning sickness, 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.
Data availability
All mass spectrometry raw data is deposited and made available via the PRIDE archive under accessions: PXD010416, PXD010417, PXD010418, PXD010420, PDX010428. Source files have been provided for all figures.
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Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome, part 1Publicly available at EBI PRIDE (accession no. PXD010416).
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Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome, part 2Publicly available at EBI PRIDE (accession no. PXD010417).
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Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome, part 3Publicly available at EBI PRIDE (accession no. PXD010418).
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Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome, part 5Publicly available at EBI PRIDE (accession no. PXD010420).
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Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome, part 6Publicly available at EBI PRIDE (accession no. PXD010428).
Article and author information
Author details
Funding
National Cancer Institute (R01CA214608)
- Katherine A Donovan
- Radoslaw P Nowak
- Eric S Fischer
Damon Runyon Cancer Research Foundation (DRR-50-18)
- Eric S Fischer
Novartis
- Katherine A Donovan
- Bethany C Berry
- Eric S Fischer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Michael Rape, University of California, Berkeley, United States
Version history
- Received: May 16, 2018
- Accepted: July 28, 2018
- Accepted Manuscript published: August 1, 2018 (version 1)
- Version of Record published: September 25, 2018 (version 2)
Copyright
© 2018, Donovan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome
eLife 7:e38430.
https://doi.org/10.7554/eLife.38430
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