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Science DOI:10.1126/science.aat0572

Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN.

Publication TypeJournal Article
Year of Publication2018
AuthorsSievers, QL, Petzold, G, Bunker, RD, Renneville, A, Słabicki, M, Liddicoat, BJ, Abdulrahman, W, Mikkelsen, T, Ebert, BL, Thomä, NH
Date Published2018 Nov 02
KeywordsAdaptor Proteins, Signal Transducing, Amino Acid Sequence, CYS2-HIS2 Zinc Fingers, HEK293 Cells, Humans, Ikaros Transcription Factor, Lenalidomide, Peptide Hydrolases, Proteolysis, Proteome, Thalidomide, Ubiquitin-Protein Ligases, Ubiquitination

The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys-His (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase. We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. Our results provide a rationale for therapeutically targeting transcription factors that were previously considered undruggable.


Alternate JournalScience
PubMed ID30385546
PubMed Central IDPMC6326779
Grant ListP50 CA206963 / CA / NCI NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
P01 CA108631 / CA / NCI NIH HHS / United States
R01 HL082941 / HL / NHLBI NIH HHS / United States