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

  1. Katherine A Donovan
  2. Jian An
  3. Radoslaw P Nowak
  4. Jingting C Yuan
  5. Emma C Fink
  6. Bethany C Berry
  7. Benjamin L Ebert
  8. Eric S Fischer  Is a corresponding author
  1. Dana-Farber Cancer Institute, United States
  2. 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.

The following data sets were generated

Article and author information

Author details

  1. Katherine A Donovan

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  2. Jian An

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  3. Radoslaw P Nowak

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  4. Jingting C Yuan

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  5. Emma C Fink

    Division of Hematology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6589-8558
  6. Bethany C Berry

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  7. Benjamin L Ebert

    Division of Hematology, Brigham and Women's Hospital, Boston, MA, United States
    Competing interests
    No competing interests declared.
  8. Eric S Fischer

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    eric_fischer@dfci.harvard.edu
    Competing interests
    Eric S Fischer, is a member of the scientific advisory board of C4 Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7337-6306

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

  1. Michael Rape, University of California, Berkeley, United States

Publication history

  1. Received: May 16, 2018
  2. Accepted: July 28, 2018
  3. Accepted Manuscript published: August 1, 2018 (version 1)
  4. 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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  1. Katherine A Donovan
  2. Jian An
  3. Radoslaw P Nowak
  4. Jingting C Yuan
  5. Emma C Fink
  6. Bethany C Berry
  7. Benjamin L Ebert
  8. Eric S Fischer
(2018)
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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