Jevtic, P.; Witus, S. R.; McCloud, D. M.; Yang, Z.; Milunevic Jevtic, A.; Roh, H.; Rape, M.

While proteasomes are best known for eliminating defective proteins or turning off signaling pathways, they also enable crucial cellular activities. Critical among these, proteasomes allow cells to initiate gene expression, but underlying targets and regulatory mechanisms remain poorly understood. Here, we report that proteasomes drive the systemic degradation of repressive transcription factors to eject TLE/Groucho-family co-repressors from chromatin and thereby constantly free transcription start sites for activator binding. This circuitry requires the E3 ligase SCF-FBXL14, which modifies its targets dependent on presentation by TLEs, but independently of their identity. The continuous cycling of co-repressors off chromatin, as achieved by systemic turnover of a protein family, is essential for stem cells to translate developmental cues into lineage-specific gene expression, and it is disrupted by cancer mutations in TLE1 that impair SCFFBXL14-recruitment. We conclude that systemic degradation of repressive transcription factors establishes co-repressor dynamics required for genes expression and cell fate specification.