UPS writes a new saga of SAGA

Abstract

SAGA (Spt-Ada-Gcn5-Acetyltransferase), an evolutionarily conserved transcriptional co-activator among eukaryotes, is a large multi-subunit protein complex with two distinct enzymatic activities, namely HAT (Histone acetyltransferase) and DUB (De-ubiquitinase), and is targeted to the promoter by the gene-specific activator proteins for histone covalent modifications and PIC (Pre-initiation complex) formation in enhancing transcription (or gene activation). Targeting of SAGA to the gene promoter is further facilitated by the 19S RP (Regulatory particle) of the 26S proteasome (that is involved in targeted degradation of protein via ubiquitylation) in a proteolysis-independent manner. Moreover, SAGA is also recently found to be regulated by the 26S proteasome in a proteolysis-dependent manner via the ubiquitylation of its Sgf73/ataxin-7 component that is required for SAGA's integrity and DUB activity (and hence transcription), and is linked to various diseases including neurodegenerative disorders and cancer. Thus, SAGA itself and its targeting to the active gene are regulated by the UPS (Ubiquitin-proteasome system) with implications in diseases.

Keywords: SAGA; Sgf73 and ataxin-7; Transcription; UPS.

Figure 1:

Schematic diagram showing transcription initiation. UAS, upstream activating sequence; TBP, TATA-box binding protein; GTF, general transcription factor; ORF, open reading frame; HAT, histone acetyltransferase; and DUB, de-ubiquitylase.

Figure 2:

Schematic diagram showing different components and modules of SAGA. SPT, suppressor of Ty element; and TAF, TBP-associated factor.

Figure 3:

Schematic diagram for ubiquitylation and 26S proteasomal degradation of the substrate protein. The E1 activating enzyme forms a thio-ester bond with 76 amino acids long ubiquitin (Ub) followed by binding with E2 conjugating enzyme, and subsequently, C-terminal forms an isopeptide bond with lysine on the substrate protein with the help of an E3 ubiquitin ligase. This process continues for multiple cycles to generate poly-ubiquitylated protein which is then targeted for degradation by the 26S proteasome complex. 19S RP, 19S regulatory particle; and 20S CP, 20S core particle. ATP, Adenosine triphosphate; and ADP, Adenosine diphosphate.

Figure 4:

Schematic diagram showing UPS (Ubiquitin-proteasome system) regulation of SAGA. Free and excess Sgf73/ataxin-7 impairs DUB-containing SAGA assembly by competing with Sgf73-associated, DUB-depleted, SAGA to favor the formation of DUB outside SAGA. The ubiquitylation and proteasomal degradation of free/excess Sgf73/ataxin-7 allows Sgf73-associated and DUB-depleted form of SAGA to form fully assembled DUB-containing SAGA.