DNA activates the Nse2/Mms21 SUMO E3 ligase in the Smc5/6 complex

Varejão, Nathalia; Ibars, Eva; Lascorz, Jara; Colomina, Neus; Torres-Rosell, Jordi; Reverter, David

doi:10.15252/embj.201798306

Cited by 46 publications

(57 citation statements)

References 65 publications

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“…PolySUMOylation in turn primes the complexes for StUbL-mediated proteolytic or nonproteolytic ubiquitylation and displacement from chromatin in conjunction with the p97 machinery. DNA can directly trigger SUMOylation, as exemplified by DNA-dependent activation of the NSMCE2/Mms21 ligase in the SMC5/6 complex (Varejao et al, 2018). A key function of chain-trimming SUMO isopeptidases would therefore be to protect the complexes from polySUMOylation until release should occur.…”

Section: Discussionmentioning

confidence: 99%

SUMO Chains Rule on Chromatin Occupancy

Keiten-Schmitz

Schunck

2020

Front. Cell Dev. Biol.

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The dynamic and reversible post-translational modification of proteins and protein complexes with the ubiquitin-related SUMO modifier regulates a wide variety of nuclear functions, such as transcription, replication and DNA repair. SUMO can be attached as a monomer to its targets, but can also form polymeric SUMO chains. While monoSUMOylation is generally involved in the assembly of protein complexes, multi-or polySUMOylation may have very different consequences. The evolutionary conserved paradigmatic signaling process initiated by multi-or polySUMOylation is the SUMO-targeted Ubiquitin ligase (StUbL) pathway, where the presence of multiple SUMO moieties primes ubiquitylation by the mammalian E3 ubiquitin ligases RNF4 or RNF111, or the yeast Slx5/8 heterodimer. The mammalian SUMO chain-specific isopeptidases SENP6 or SENP7, or yeast Ulp2, counterbalance chain formation thereby limiting StUbL activity. Many facets of SUMO chain signaling are still incompletely understood, mainly because only a limited number of polySUMOylated substrates have been identified. Here we summarize recent work that revealed a highly interconnected network of candidate polySUMO modified proteins functioning in DNA damage response and chromatin organization. Based on these datasets and published work on distinct polySUMO-regulated processes we discuss overarching concepts in SUMO chain function. We propose an evolutionary conserved role of polySUMOylation in orchestrating chromatin dynamics and genome stability networks by balancing chromatin-residency of protein complexes. This concept will be exemplified in processes, such as centromere/kinetochore organization, sister chromatid cohesion, DNA repair and replication.

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Section: Discussionmentioning

confidence: 99%

SUMO Chains Rule on Chromatin Occupancy

Keiten-Schmitz

Schunck

2020

Front. Cell Dev. Biol.

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“…Incorporation of Smc5-Smc6 into foci may enable trans SUMOylation of its subunits by Nse2 due to the increased local concentration of the complex. Indeed, a recent in vitro study revealed that budding yeast Nse4 is SUMOylated in trans in a DNA-stimulated manner by Smc5-Smc6-Nse2 (47). Thus, the defective recruitment and/or loading of Smc5-Smc6 at DNA lesions in cells lacking Brc1 or Nse5-Nse6 can explain the strongly reduced MMS-induced Nse4 SUMOylation in these cells.…”

Section: Discussionmentioning

confidence: 99%

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

Oravcová

Gadaleta

Nie

et al. 2019

Molecular and Cellular Biology

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As genetic instability drives disease or loss of cell fitness, cellular safeguards have evolved to protect the genome, especially during sensitive cell cycle phases, such as DNA replication. Fission yeast Brc1 has emerged as a key factor in promoting cell survival when replication forks are stalled or collapsed. Brc1 is a multi-BRCT protein that is structurally related to the budding yeast Rtt107 and human PTIP DNA damage response factors, but functional similarities appear limited. Brc1 is a dosage suppressor of a mutation in the essential Smc5-Smc6 genome stability complex and is thought to act in a bypass pathway. In this study, we reveal an unexpectedly intimate connection between Brc1 and Smc5-Smc6 function. Brc1 is required for the accumulation of the Smc5-Smc6 genome stability complex in foci during replication stress and for activation of the intrinsic SUMO ligase activity of the complex by collapsed replication forks. Moreover, we show that the chromatin association and SUMO ligase activity of Smc5-Smc6 require the Nse5-Nse6 heterodimer, explaining how this nonessential cofactor critically supports the DNA repair roles of Smc5-Smc6. We also found that Brc1 interacts with Nse5-Nse6, as well as gamma-H2A, so it can tether Smc5-Smc6 at replicative DNA lesions to promote survival.

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“…In their present study, Varejão et al (2018) present exciting new insights into how the SUMO E3 ligase activity of yeast Nse2 is stimulated by the presence of DNA when in complex with SMC5. While enhancement was found also with doublestranded DNA, the experiments revealed a clear preference for single-stranded DNA, which perfectly fits with the role of Nse2dependent sumoylation in DNA damage repair.…”

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confidence: 78%

“…Indeed, mutating these basic residues in SMC5 sensitized yeast cells to DNA damage and reduced Nse2‐dependent substrate sumoylation in vivo . In their model, Varejão et al () thus propose that a positively charged patch in SMC5 interacts with the negatively charged DNA, leading to a conformational change that activates Nse2s E3 ligase activity.…”

Section: Dna‐dependent Sumo E3 Ligase Activation Of the Nse2‐smc5‐6 Cmentioning

confidence: 99%