Comprehensive degron mapping in human transcription factors.

Systematic mapping across 1626 human transcription factors identifies thousands of known and previously unidentified degrons, including latent zinc-finger degrons unveiled by melanoma-linked somatic mutations.

• Why it matters: Degrons determine which transcription factors are targeted by the ubiquitin-proteasome system, but their full sequence landscape and how variants alter degron exposure remain incompletely defined.
• What they did: The study systematically maps degrons in all 1626 human transcription factors, characterizing degron sequence properties and testing how placing active degrons in exposed, intrinsically disordered regions affects transcription factor abundance.
• The result: Active degrons in exposed/disordered regions modulate transcription factor abundance, and melanoma-linked mutations are linked to unfolding that exposes a latent degron; variant effects correlate with degron potency, and >60% of predicted activation domains overlap strong degrons while acidic residues can counter potency.

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