A ubiquitin-selective AAA-ATPase mediates transcriptional switching by remodeling a repressor-promoter DNA complex

Switches between different phenotypes and their underlying states of gene transcription occur as cells respond to intrinsic developmental cues or adapt to changing environmental conditions. Post-translational modification of the master regulatory transcription factors that define the initial phenotype is a common strategy to direct such transitions. Emerging evidence indicates that the modification of key transcription factors by the small polypeptide ubiquitin plays a central role in many of these transitions1, 2. However, the molecular mechanisms by which ubiquitination regulates the switching of promoters between active and inactive states are largely unknown. Ubiquitination of the yeast transcriptional repressor α2 is necessary to evoke the transition between mating-types3, and here, we dissected the impact of this modification on α2 dynamics at its target promoters. The ubiquitination of α2 does not alter DNA occupancy by depleting the existing pool of the transcription factor, despite its well-characterized function in directing repressor turnover. Rather, α2 ubiquitination plays a direct role in the rapid removal of the repressor from its DNA targets. This disassembly of α2 from DNA depends on the ubiquitin-selective AAA-ATPase Cdc48. Our findings expand the functional targets of Cdc48 to active transcriptional regulatory complexes in the nucleus, a far broader role than previously anticipated. These data reveal an ubiquitin-dependent extraction pathway for dismantling transcription factor-DNA complexes and provide an archetype for the regulation of transcriptional switching events by ubiquitination.