SUMO-targeted ubiquitin ligase activity can either suppress or promote genome instability, depending on the nature of the DNA lesion

Abstract

The posttranslational modifiers SUMO and ubiquitin critically regulate the DNA damage response (DDR). Important crosstalk between these modifiers at DNA lesions is mediated by the SUMO-targeted ubiquitin ligase (STUbL), which ubiquitinates SUMO chains to generate SUMO-ubiquitin hybrids. These SUMO-ubiquitin hybrids attract DDR proteins able to bind both modifiers, and/or are degraded at the proteasome. Despite these insights, specific roles for SUMO chains and STUbL in the DDR remain poorly defined. Notably, fission yeast defective in SUMO chain formation exhibit near wild-type resistance to genotoxins and moreover, have a greatly reduced dependency on STUbL activity for DNA repair. Based on these and other data, we propose that a critical role of STUbL is to antagonize DDR-inhibitory SUMO chain formation at DNA lesions. In this regard, we identify a SUMO-binding Swi2/Snf2 translocase called Rrp2 (ScUls1) as a mediator of the DDR defects in STUbL mutant cells. Therefore, in support of our proposal, SUMO chains attract activities that can antagonize STUbL and other DNA repair factors. Finally, we find that Taz1TRF1/TRF2-deficiency triggers extensive telomeric poly-SUMOylation. In this setting STUbL, together with its cofactor Cdc48p97, actually promotes genomic instability caused by the aberrant processing of taz1Δ telomeres by DNA repair factors. In summary, depending on the nature of the initiating DNA lesion, STUbL activity can either be beneficial or harmful.

The nuclear pore primes recombination-dependent DNA synthesis at arrested forks by promoting SUMO removal

“…RDR and anchorage, but not fork-integrity, are impaired by the loss of the Slx5-Slx8 STUbL pathway. Depending on the nature of DNA lesions, the S. pombe Slx8 STUbL either suppresses or promotes genome instability 53 . Also, Slx8 prevents uncontrolled HR at the constitutive RTS1-RFB 54 .…”

“…promoter was replaced by a weaker constitutive promoter 53 and a pmt3-KallR mutant (SUMO-KallR) in which all internal Lys are mutated to Arg to prevent poly-SUMOylation 55 . Pli1-dependent SUMO chain formation is enhanced by the interaction between the single E2 SUMO conjugating enzyme Ubc9 and SUMO.…”

Brc1 Promotes the Focal Accumulation and SUMO Ligase Activity of Smc5-Smc6 during Replication Stress

“…6). In general, the concentration or forced nucleation of SUMO pathway components leads to increased local activity (51)(52)(53). Thus, although not tested here due to the lack of an appropriate substrate, it is likely that other proteins at collapsed replication forks in the vicinity of Smc5-Smc6-Nse2 foci also undergo increased regulatory SUMOylation.…”

SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

“…STUbLs are described to facilitate Top1cc processing in budding, fission yeast, and mammalian cells (Nie et al, 2017;Sharma et al, 2017;Sun et al, 2019). The Slx5-Slx8 STUbL promotes repair in a pathway parallel to Tdp1 ( Figure S1F), as also observed in fission yeast (Nie et al, 2017). Mixed SUMO-Ub chains generated by the Slx5-Slx8 complex could, on the one hand, recruit Cdc48-Wss1 ( Figure 6), as suggested by the epistatic relationship of wss1D with the tdp1D slx5D mutant ( Figure S1F).…”