The SAGA complex regulates early steps in transcription via its deubiquitylase module subunit USP22

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.

Deubiquitination complex platform: A plausible mechanism for regulating the substrate specificity of deubiquitinating enzymes

“… DUB Scaffold protein/complex Substrate Ref. UBP1 UAF1/FANCI FANCD2 29 UBP7 TRIM RIP1 30 BUB3 FOXA1 31 UBP8 Sgf11/Sus1/Sgf73 H2B 21 ESCRT-0 complex EGFR 22 , 23 BRUCE BRIT1 24 Clec16a/NRDP1 Parkin 32 UBP10 TANK/MCPIP1 TRAF6 25 G3BP1 family RPS2,3,10 33 DNAbound AR – 3 UBP11 SWI/SNF chromatin-remodelling complex/HDAC6/lymphoid transcription-factor REQ – 3 UBP12 UAF1/WDR20 – 34 GIGANTEA ZTL 35 UBP13 GIGANTEA ZTL 35 UBP22 SAGA complex H2B 14 , 36 TFTC complex H2B 14 UBP25 TNKS1 GLUT4 37 UBP29 SCP1 Snail …”

SAGA-Dependent Histone H2Bub1 Deubiquitination Is Essential for Cellular Ubiquitin Balance during Embryonic Development

“…Moreover, in addition to their functions as potential epigenetic regulators, USP22-, USP27X-, and USP51-containing DUB modules also have non-histone substrates, including TRF1 [58], cyclin D1 [59], FBP1 [60], SIRT1 [61,62], HES1 [63], SNAIL1 [64], and ZEB1 [65]. The SAGA DUB activity has also been implicated in deubiquitination several other cellular proteins, such as heat HSPA5 (also known as BIP or GRP78), receptor-interacting protein kinase 3 (RIPK3), Mediator complex subunits MED16 and MED24, and the largest subunit of Pol II, RPB1 [66][67][68][69]. All these additional deubiquitination activities may also participate to constitute the free cellular ub pool.…”