Comprehensive degron mapping in human transcription factors

Gene expression is regulated by the targeted degradation of transcription factors through the ubiquitin-proteasome system. Transcription factors destined for degradation are recognized by E3 ubiquitin-protein ligases through motifs termed degrons, embedded within the sequence. In this study, we systematically map degrons in all 1626 human transcription factors. We find thousands of both known and previously unidentified degrons and characterize their sequence properties. Active degrons placed within exposed and intrinsically disordered regions contribute to modulating the abundance of the transcription factors, while the most common somatic mutations that are linked to skin cutaneous melanoma lead to unfolding and exposure of a latent degron buried in the zinc finger structure. We present examples of compartment-specific degrons and demonstrate that variant effects in transcription factors correlate with degron potency. Last, we show that while >60% of all predicted transcriptional activation domains overlap with strong degrons, acidic residues within the remaining transactivating regions counter the degron potency, showing how degrons can shape the transcription factor sequence landscape.