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.
-
Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome, part 1Publicly available at EBI PRIDE (accession no. PXD010416).
-
Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome, part 2Publicly available at EBI PRIDE (accession no. PXD010417).
-
Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome, part 3Publicly available at EBI PRIDE (accession no. PXD010418).
-
Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome, part 5Publicly available at EBI PRIDE (accession no. PXD010420).
-
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.
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
-
- 31,867
- views
-
- 5,190
- downloads
-
- 366
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome
eLife 7:e38430.
https://doi.org/10.7554/eLife.38430
Further reading
-
- Biochemistry and Chemical Biology
- Cancer Biology
Cancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or inhibit checkpoint kinases involved in the DNA damage response. Thus far, treatments that combine these two strategies have shown promise but also have severe adverse effects. To identify novel, better-tolerated anticancer combinations, we screened a collection of plant extracts and found two natural compounds from the plant, Psoralea corylifolia, that synergistically inhibit cancer cell proliferation. Bakuchiol inhibited DNA replication and activated the checkpoint kinase CHK1 by targeting DNA polymerases. Isobavachalcone interfered with DNA double-strand break repair by inhibiting the checkpoint kinase CHK2 and DNA end resection. The combination of bakuchiol and isobavachalcone synergistically inhibited cancer cell proliferation in vitro. Importantly, it also prevented tumor development in xenografted NOD/SCID mice. The synergistic effect of inhibiting DNA replication and CHK2 signaling identifies a vulnerability of cancer cells that might be exploited by using clinically approved inhibitors in novel combination therapies.
-
- Biochemistry and Chemical Biology
- Cell Biology
Stem cell differentiation involves a global increase in protein synthesis to meet the demands of specialized cell types. However, the molecular mechanisms underlying this translational burst and the involvement of initiation factors remains largely unknown. Here, we investigate the role of eukaryotic initiation factor 3 (eIF3) in early differentiation of human pluripotent stem cell (hPSC)-derived neural progenitor cells (NPCs). Using Quick-irCLIP and alternative polyadenylation (APA) Seq, we show eIF3 crosslinks predominantly with 3’ untranslated region (3’-UTR) termini of multiple mRNA isoforms, adjacent to the poly(A) tail. Furthermore, we find that eIF3 engagement at 3’-UTR ends is dependent on polyadenylation. High eIF3 crosslinking at 3’-UTR termini of mRNAs correlates with high translational activity, as determined by ribosome profiling, but not with translational efficiency. The results presented here show that eIF3 engages with 3’-UTR termini of highly translated mRNAs, likely reflecting a general rather than specific regulatory function of eIF3, and supporting a role of mRNA circularization in the mechanisms governing mRNA translation.
