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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.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

Matyskiela ME,Couto S,Zheng X,Lu G,Hui J,Stamp K,Drew C,Ren Y,Wang M,Carpenter A,Lee CW,Clayton T,Fang W,Lu CC,Riley M,Abdubek P,Blease K,Hartke J,Kumar G,Vessey R,Rolfe M,Hamann LG,Chamberlain PP

doi

10.1038/s41589-018-0129-x

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

981-987

issue

10

eissn

1552-4450

issn

1552-4469

pii

10.1038/s41589-018-0129-x

journal_volume

14

pub_type

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