SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate.

Abstract

Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.

• Authors: Mary E Matyskiela, Suzana Couto, Xinde Zheng, Gang Lu, Julia Hui, Katie Stamp, Clifton Drew, Yan Ren, Maria Wang, Aaron Carpenter, Chung-Wein Lee, Thomas Clayton, Wei Fang, Chin-Chun Lu, Mariko Riley, Polat Abdubek, Kate Blease, James Hartke, Gondi Kumar, Rupert Vessey, Mark Rolfe, Lawrence G Hamann, Philip P Chamberlain
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 14 Issue 10 Pg. 981-987 (10 2018) ISSN: 1552-4469 [Electronic] United States
• PMID: 30190590 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• CRBN protein, human
• Crbn protein, mouse
• DNA-Binding Proteins
• Ligands
• Nerve Tissue Proteins
• SALL4 protein, human
• Sall4 protein, mouse
• Teratogens
• Transcription Factors
• Thalidomide
• Ubiquitin-Protein Ligases
• Peptide Hydrolases
• ZFP91 protein, human

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• DNA-Binding Proteins (chemistry, genetics)
• Gene Expression Regulation
• Homozygote
• Humans
• Immunohistochemistry
• Induced Pluripotent Stem Cells
• Ligands
• Male
• Mice
• Mice, Transgenic
• Mutation
• Nerve Tissue Proteins (chemistry, genetics)
• Peptide Hydrolases (chemistry, genetics)
• Proteolysis
• Rabbits
• Teratogens (chemistry)
• Testis (metabolism)
• Thalidomide (chemistry)
• Transcription Factors (chemistry, genetics)
• Ubiquitin-Protein Ligases (metabolism)
• Zinc Fingers