Donovan, Katherine and Fischer, Eric (2018) CRL4CRBN Mediated Degradation of SALL4 Links Thalidomide Syndrome to Duane Radial Ray Syndrome. ELife., 7. ISSN 2050-084X

Abstract

First administered in the late 1950s as a mild sedative, the drug thalidomide led to the birth of thousands of children with multiple birth defects1-3. Despite their teratogenicity, thalidomide and closely related immunomodulatory drugs (IMiDs) are now a mainstay of cancer treatment4,5. Thalidomide binds to the Cullin RING E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN)6-8 and promotes ubiquitination and degradation of key therapeutic targets such as IKZF1/39-11 and Ck112 in a molecular glue like mechanism13,14. CRL4CRBN was further shown to exert ubiquitin dependent or independent functions on glutamine synthethase (GS)15, CD147-MCT116, MEIS26, and ZFP9117, however, none of these targets has been causatively linked to thalidomide embryopathies. Here we show that thalidomide, lenalidomide and pomalidomide induce degradation of the C2H2 zinc finger transcription factor SALL4, a member of the SAL family of developmental transcription factors related to the drosophila spalt homeotic transcription factor18. Heterozygous loss of function (LOF) mutations in SALL4 manifest in Duane Radial Ray and Holt-Oram syndromes19-22, developmental conditions that show striking similarities to thalidomide induced birth defects such as absence of thumbs, shortened or loss of bones in forearm, and congenital heart disease. Two reported cases of thalidomide embryopathy were later re-diagnosed to originate from familial mutations in the SALL4 gene21. Our work demonstrates that thalidomide directly targets the SALL4 protein for CRL4CRBN mediated degradation, and thereby establishes a genetic link to the plethora of developmental defects found in thalidomide syndrome.

Item Type:	Article
Date Deposited:	02 Oct 2018 00:45
Last Modified:	02 Oct 2018 00:45
URI:	https://oak.novartis.com/id/eprint/34837