Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRL4 CRBN

The small molecule drugs thalidomide, lenalidomide, and pomalidomide induce ubiquitination and proteasomal degradation of the zinc finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruitment to Cereblon (CRBN), the substrate receptor of the CRL4^CRBN E3 ubiquitin ligase. Here we screened the entire human Cys2-His2 (C2H2) zinc finger proteome for degradation by CRL4^CRBN in the presence of thalidomide analogues, identifying 11 zinc finger targets. Structural and functional characterization of the C2H2 zinc finger degron demonstrates how diverse zinc finger domains bind the promiscuous drug-CRBN interface. Computational ZF docking, in conjunction with biochemical analysis, predicts that at least 50 zinc-fingers bind the drug-CRBN complex in vitro, a larger number than previously anticipated. Functional studies demonstrate that selective degradation of zinc fingers could be tuned through compound modifications, providing a basis for the development of small molecules that degrade a wide range of zinc finger transcription factors.