The SAGA complex regulates early steps in transcription via its deubiquitylase module subunit USP22
Timothy J. Stanek, Victoria Gennaro, Mason Tracewell, Daniela Di Marcantonio, Kristen Pauley, Sabrina Butt, Christopher McNair, Feng Wang, Andrew V. Kossenkov, Karen E. Knudsen, Tauseef R. Butt, Stephen M. Sykes, Steven B. McMahon
Abstract
The SAGA coactivator complex is essential for eukaryotic transcription and comprises four distinct modules, one of which contains the ubiquitin hydrolase USP22. In yeast, the USP22 ortholog deubiquitylates H2B, resulting in Pol II Ser2 phosphorylation and subsequent transcriptional elongation. In contrast to this H2B‐associated role in transcription, we report here that human USP22 contributes to the early stages of stimulus‐responsive transcription, where USP22 is required for pre‐initiation complex (PIC) stability. Specifically, USP22 maintains long‐range enhancer–promoter contacts and controls loading of Mediator tail and general transcription factors (GTFs) onto promoters, with Mediator core recruitment being USP22‐independent. In addition, we identify Mediator tail subunits MED16 and MED24 and the Pol II subunit RBP1 as potential non‐histone substrates of USP22. Overall, these findings define a role for human SAGA within the earliest steps of transcription. In eukaryotic transcription, the SAGA coactivator subunit USP22 is commonly known for its deubiquitylation of histone H2B. Here, human USP22 is implicated in the earliest steps of transcription, where it plays a role in stabilizing the pre‐initiation complex. Loss of human USP22 affects the stability of the pre‐initiation complex, rather than histone H2B ubiquitylation, during stimulus‐responsive transcription.