Abstract
Chromatin is a highly regulated environment, and protein association with chromatin is often controlled by post‐translational modifications and the corresponding enzymatic machinery. Specifically, SUMO‐targeted ubiquitin ligases (STUbLs) have emerged as key players in nuclear quality control, genome maintenance, and transcription. However, how STUbLs select specific substrates among myriads of SUMOylated proteins on chromatin remains unclear. Here, we reveal a remarkable co‐localization of the budding yeast STUbL Slx5/Slx8 and ubiquitin at seven genomic loci that we term “ubiquitin hotspots”. Ubiquitylation at these sites depends on Slx5/Slx8 and protein turnover on the Cdc48 segregase. We identify the transcription factor‐like Ymr111c/Euc1 to associate with these sites and to be a critical determinant of ubiquitylation. Euc1 specifically targets Slx5/Slx8 to ubiquitin hotspots via bipartite binding of Slx5 that involves the Slx5 SUMO‐interacting motifs and an additional, novel substrate recognition domain. Interestingly, the Euc1‐ubiquitin hotspot pathway acts redundantly with chromatin modifiers of the H2A.Z and Rpd3L pathways in specific stress responses. Thus, our data suggest that STUbL‐dependent ubiquitin hotspots shape chromatin during stress adaptation.
Highlights
SUMO-targeted ubiquitin ligases (STUbLs) modify SUMOylated proteins with ubiquitin and thereby transfer substrates from the SUMO to the ubiquitin pathway (Sriramachandran & Dohmen, 2014)
STUbLs combine binding to SUMOylated proteins via SUMO-interacting motifs (SIMs) with ubiquitin ligase activity (Prudden et al, 2007; Sun et al, 2007; Uzunova et al, 2007; Xie et al, 2007)
A hallmark of several STUbL substrates is modification with SUMO chains (Uzunova et al, 2007; Tatham et al, 2008), but it has been suggested for the human STUbLs RNF4 and Arkadia/RNF111, as well as for Drosophila Degringolade/ Dgrn that they might use additional SUMO-independent interactions for substrate recognition (Abed et al, 2011; Groocock et al, 2014; Kuo et al, 2014; Sun et al, 2014; Thomas et al, 2016)
Summary
SUMO-targeted ubiquitin ligases (STUbLs) modify SUMOylated proteins with ubiquitin and thereby transfer substrates from the SUMO (small ubiquitin-like modifier) to the ubiquitin pathway (Sriramachandran & Dohmen, 2014). STUbLs combine binding to SUMOylated proteins via SUMO-interacting motifs (SIMs) with ubiquitin ligase activity (Prudden et al, 2007; Sun et al, 2007; Uzunova et al, 2007; Xie et al, 2007). Apart from this defining feature, the STUbL enzyme family is highly heterogeneous, as is the regulation of each member, even though functional aspects appear to be conserved (Sriramachandran & Dohmen, 2014). In case of the prototypical STUbL, budding yeast Slx5/Slx, no substrate recognition elements have been characterized other than its SUMO-interacting motifs
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