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
- Cited 72
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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.
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
Publication 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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Further reading
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- Biochemistry and Chemical Biology
La-related protein 4 (LARP4) directly binds both poly(A) and poly(A)-binding protein (PABP). LARP4 was shown to promote poly(A) tail (PAT) lengthening and stabilization of individual mRNAs presumably by protection from deadenylation (Mattijssen et al., 2017). We developed a nucleotide resolution transcriptome-wide, single molecule SM-PAT-seq method. This revealed LARP4 effects on a wide range of PAT lengths for human mRNAs and mouse mRNAs from LARP4 knockout (KO) and control cells. LARP4 effects are clear on long PAT mRNAs but become more prominent at 30–75 nucleotides. We also analyzed time courses of PAT decay transcriptome-wide and for ~200 immune response mRNAs. This demonstrated accelerated deadenylation in KO cells on PATs < 75 nucleotides and phasing consistent with greater PABP dissociation in the absence of LARP4. Thus, LARP4 shapes PAT profiles throughout mRNA lifespan with impact on mRNA decay at short lengths known to sensitize PABP dissociation in response to deadenylation machinery.
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- Biochemistry and Chemical Biology
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