Genome stability roles of SUMO-targeted ubiquitin ligases

Abstract

Post-translational modification of the cell's proteome by ubiquitin and ubiquitin-like proteins provides dynamic functional regulation. Ubiquitin and SUMO are well-studied post-translational modifiers that typically impart distinct effects on their targets. The recent discovery that modification by SUMO can target proteins for ubiquitination and proteasomal degradation sets a new paradigm in the field, and offers insights into the roles of SUMO and ubiquitin in genome stability.

Figure 1. Schematic representation of STUbL protein architecture

The heterodimeric yeast STUbLs are exemplified by the fission yeast Slx8-Rfp complex. Protein domains in both Slx8 and Rfp that are critical for function, including the canonical RING domain, the two SIMs and a C-terminal stretch of 6 hydrophobic amino acids (Ψ₆) are incorporated into a single polypeptide chain in mammalian STUbLs, as exemplified by human RNF4. Respective protein sizes are given in brackets, and sequences of the conserved SIM are indicated above the SIM protein boxes, where Ψ is a hydrophobic amino acid.

Figure 2. Proposed function of the fission yeast Slx8-Rfp STUbL complex and relationship to the SUMO and ubiquitin systems

A specific cellular protein (protein X) exists in a sensitive balance between its sumoylated and non-sumoylated form, with only a minor fraction of its pool being SUMO-modified. This balance is maintained by the activities of SUMO modifying E1 (Fub2/Rad31), E2 (Ubc9), and E3s (Pli1), and either of two SUMO specific proteases (Ulp1/2). Slx8-Rfp recognizes sumoylated forms of protein X via Rfp-mediated non-covalent SUMO-SIM interactions. Aided by ubiquitin E1 and E2s, Slx8 ubiquitinates the sumoylated protein X, either directly and/or on the SUMO moieties, which targets protein X for degradation. After degradation, SUMO and ubiquitin likely return to their cellular pools to be re-used in a new round of SUMO and/or ubiquitin protein modification. SUMO moieties are denoted by S and ubiquitin groups by Ub.

Figure 3. Overview of STUbL functions in genome stability and transcription

See text for details. The replisome is denoted by REP, and telomere binding proteins are denoted by TEBP.