Mec1-dependent phosphorylation of Mms21 modulates its SUMO ligase activity

Carlborg, Kristian K.; Kanno, Takaharu; Carter, Sidney D.; Sjögren, Camilla

doi:10.1016/j.dnarep.2015.01.006

Cited by 8 publications

(7 citation statements)

References 67 publications

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“…Our results suggest that phosphorylation of serine 261 of Mms21 promoted by the Mec1 and Tel1 protein kinases in response to DNA damage, and also by PKA, induces SUMOylation of Snf1 and thereby inhibits SNF1 function, leading to reduced expression of genes for respiration and to the increased HXT gene expression necessary for fermentation (summarized in Figure 7 ). Recently, Carlborg et al published an investigation of Mms21 regulation under both ambient conditions and after DNA damage (Carlborg et al, 2015). In accordance with the results presented here, they report that Mms21 is phosphorylated on both S260 and S261.…”

Section: Discussionmentioning

confidence: 99%

Cross-Talk between Carbon Metabolism and the DNA Damage Response in S. cerevisiae

et al. 2015

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Yeast cells with DNA damage avoid respiration, presumably because products of oxidative metabolism can be harmful to DNA. We show that DNA damage inhibits the activity of the Snf1 (AMP-activated) protein kinase (AMPK), which activates expression of genes required for respiration. Glucose and DNA damage upregulate SUMOylation of Snf1, catalyzed by the SUMO E3-ligase Mms21, which inhibits SNF1 activity. The DNA damage checkpoint kinases Mec1/ATR and Tel1/ATM, as well as the nutrient sensing protein kinase A (PKA), regulate Mms21 activity towards Snf1. Mec1 and Tel1 are required for two SNF1-regulated processes—glucose sensing and ADH2 gene expression—even without exogenous genotoxic stress. Our results imply that inhibition of Snf1 by SUMOylation is a mechanism by which cells lower their respiration in response to DNA damage. This raises the possibility that activation of DNA damage checkpoint mechanisms could contribute to aerobic fermentation (Warburg effect), a hallmark of cancer cells.

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Section: Discussionmentioning

confidence: 99%

Cross-Talk between Carbon Metabolism and the DNA Damage Response in S. cerevisiae

et al. 2015

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“…Alternatively, phosphorylation by Rad53 of Pol ε, the Smc5/6 complex or other neighbouring proteins might increase the efficiency of SUMOylation (either by stimulating the catalytic activity of Mms21 or by making K571 a better substrate for modification) or promote the stability of the modification (by sheltering or protecting the modification from SUMO-proteases). While several subunits of the Smc5/6 complex and Pol ε are phosphorylated following HU incubation such as Dpb2, Dpb3, Dpb4, Mms21, Nse4 and Nse6 [22, 47, 101], future work will address whether these are responsible for the SUMOylation of Pol2 in HU.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, the S phase checkpoint also modulates the SUMOylation response. In budding yeast, Mec1 and Tel1 checkpoint kinases phosphorylate Mms21, and stimulate the SUMOylation of Snf1 [47, 48]. Similarly, human FANCI and FANCD2 are SUMOylated in response to replication fork stalling in an ATR-dependent manner [49].…”

Section: Introductionmentioning

confidence: 99%

The S phase checkpoint promotes the Smc5/6 complex dependent SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε

et al. 2019

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Replication fork stalling and accumulation of single-stranded DNA trigger the S phase checkpoint, a signalling cascade that, in budding yeast, leads to the activation of the Rad53 kinase. Rad53 is essential in maintaining cell viability, but its targets of regulation are still partially unknown. Here we show that Rad53 drives the hyper-SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε, principally following replication forks stalling induced by nucleotide depletion. Pol2 is the main target of SUMOylation within the replisome and its modification requires the SUMO-ligase Mms21, a subunit of the Smc5/6 complex. Moreover, the Smc5/6 complex co-purifies with Pol ε, independently of other replisome components. Finally, we map Pol2 SUMOylation to a single site within the N-terminal catalytic domain and identify a SUMO-interacting motif at the C-terminus of Pol2. These data suggest that the S phase checkpoint regulate Pol ε during replication stress through Pol2 SUMOylation and SUMO-binding ability

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“…Thus, Mms21 may support mcm10-1 survival directly through sumoylation of Bir1. Interestingly, phosphorylation of Mms21 by the Mec1 checkpoint kinase stimulates its SUMO ligase activity (Carlborg et al, 2015). Since Rad53, a downstream target of Mec1, is activated in mcm10-1 cells, checkpoint signaling may promote Mms21-dependent sumoylation of chromatin-associated proteins and relay the stress signal from replication forks to other chromosome organizing regions, such as centromeres (Figure 7C).…”

Section: Discussionmentioning

confidence: 99%

Slx5/Slx8 Promotes Replication Stress Tolerance by Facilitating Mitotic Progression

et al. 2016

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SUMMARY Loss of minichromosome maintenance protein 10 (Mcm10) causes replication stress. We uncovered that S. cerevisiae mcm10-1 mutants rely on the E3 SUMO ligase Mms21 and the SUMO-targeted ubiquitin ligase complex Slx5/8 for survival. Using quantitative mass spectrometry, we identified changes in the SUMO proteome of mcm10-1 mutants and revealed candidates regulated by Slx5/8. Such candidates included subunits of the chromosome passenger complex (CPC), Bir1 and Sli15, known to facilitate spindle assembly checkpoint (SAC) activation. We show here that Slx5 counteracts SAC activation in mcm10-1 mutants under conditions of moderate replication stress. This coincides with the proteasomal degradation of sumoylated Bir1. Importantly, Slx5-dependent mitotic relief was not only triggered by Mcm10 deficiency but also by treatment with low doses of the alkylating drug methyl methanesulfonate. Based on these findings, we propose a model in which Slx5/8 allows for passage through mitosis when replication stress is tolerable.

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Mec1-dependent phosphorylation of Mms21 modulates its SUMO ligase activity

Cited by 8 publications

References 67 publications

Cross-Talk between Carbon Metabolism and the DNA Damage Response in S. cerevisiae

Cross-Talk between Carbon Metabolism and the DNA Damage Response in S. cerevisiae

The S phase checkpoint promotes the Smc5/6 complex dependent SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε

Slx5/Slx8 Promotes Replication Stress Tolerance by Facilitating Mitotic Progression

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