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

Version 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.

Metrics

  • 29,390
    Page views
  • 4,837
    Downloads
  • 276
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.38430

Further reading

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Ivan Corbeski, Pablo Andrés Vargas-Rosales ... Amedeo Caflisch
    Research Article

    The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N6-methyladenosine (m6A) modifications on messenger RNA (mRNA) in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor S-adenosylmethionine (SAM). Here, we study the MTase mechanism of METTL3-14 by a combined experimental and multiscale simulation approach using bisubstrate analogues (BAs), conjugates of a SAM-like moiety connected to the N6-atom of adenosine. Molecular dynamics simulations based on crystal structures of METTL3-14 with BAs suggest that the Y406 side chain of METTL3 is involved in the recruitment of adenosine and release of m6A. A crystal structure with a BA representing the transition state of methyl transfer shows a direct involvement of the METTL3 side chains E481 and K513 in adenosine binding which is supported by mutational analysis. Quantum mechanics/molecular mechanics (QM/MM) free energy calculations indicate that methyl transfer occurs without prior deprotonation of adenosine-N6. Furthermore, the QM/MM calculations provide further support for the role of electrostatic contributions of E481 and K513 to catalysis. The multidisciplinary approach used here sheds light on the (co)substrate binding mechanism, catalytic step, and (co)product release, and suggests that the latter step is rate-limiting for METTL3. The atomistic information on the substrate binding and methyl transfer reaction of METTL3 can be useful for understanding the mechanisms of other RNA MTases and for the design of transition state analogues as their inhibitors.

    1. Biochemistry and Chemical Biology
    2. Developmental Biology
    Zhi Li, Yuedi Wang ... Zeyang Zhou
    Research Article

    Imidacloprid is a global health threat that severely poisons the economically and ecologically important honeybee pollinator, Apis mellifera. However, its effects on developing bee larvae remain largely unexplored. Our pilot study showed that imidacloprid causes developmental delay in bee larvae, but the underlying toxicological mechanisms remain incompletely understood. In this study, we exposed bee larvae to imidacloprid at environmentally relevant concentrations of 0.7, 1.2, 3.1, and 377 ppb. There was a marked dose-dependent delay in larval development, characterized by reductions in body mass, width, and growth index. However, imidacloprid did not affect on larval survival and food consumption. The primary toxicological effects induced by elevated concentrations of imidacloprid (377 ppb) included inhibition of neural transmission gene expression, induction of oxidative stress, gut structural damage, and apoptosis, inhibition of developmental regulatory hormones and genes, suppression of gene expression levels involved in proteolysis, amino acid transport, protein synthesis, carbohydrate catabolism, oxidative phosphorylation, and glycolysis energy production. In addition, we found that the larvae may use antioxidant defenses and P450 detoxification mechanisms to mitigate the effects of imidacloprid. Ultimately, this study provides the first evidence that environmentally exposed imidacloprid can affect the growth and development of bee larvae by disrupting molting regulation and limiting the metabolism and utilization of dietary nutrients and energy. These findings have broader implications for studies assessing pesticide hazards in other juvenile animals.