Screen for degrons in human transcription factors

Gene expression is regulated by the targeted degradation of transcription factors through theubiquitin-proteasome system. Transcription factors destined for degradation are recognized byE3 ubiquitin-protein ligases through short motifs termed degrons, embedded within thesequence. In this study, we systematically map degrons in all 1,626 human transcription factors.We find thousands of both known and previously unidentified degrons and characterize theirsequence properties. Degrons placed within exposed and intrinsically disordered regionsregulate the cellular abundance of the transcription factors, while the most common somaticmutations that are linked to skin cutaneous melanoma lead to unfolding and exposure of aburied degron in zinc fingers. We present examples of compartment specific degrons anddemonstrate that variant effects in transcription factors correlate with degron potency. Finally,we show that while >60% of all predicted transcriptional activation domains overlap withstrong degrons, acidic residues within the remaining transactivating regions counter the degronpotency.