SUMO-Chain-Regulated Proteasomal Degradation Timing Exemplified in DNA Replication Initiation
| Autor: | Federica Castellucci, Ivan Psakhye, Dana Branzei |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
DNA Replication
Proteasome Endopeptidase Complex Saccharomyces cerevisiae Proteins Time Factors DNA replication initiation Cdc48 segregase protein-group modification Ubiquitin-Protein Ligases Mutant genetic processes DDK Cell Cycle Proteins Replication Origin macromolecular substances Slx5/8 Saccharomyces cerevisiae Protein Serine-Threonine Kinases Origin of replication environment and public health Article 03 medical and health sciences 0302 clinical medicine Ubiquitin Minichromosome maintenance Valosin Containing Protein Gene Expression Regulation Fungal ubiquitin Endopeptidases DNA Fungal Molecular Biology 030304 developmental biology 0303 health sciences biology DNA replication Sumoylation Cell Biology SUMO chains STUbL-mediated proteasomal degradation Ubiquitin ligase Chromatin Cell biology enzymes and coenzymes (carbohydrates) SUMO SENP/Ulp proteases Mutation biology.protein health occupations 030217 neurology & neurosurgery |
| Zdroj: | Molecular Cell |
| ISSN: | 1097-4164 1097-2765 |
| Popis: | Summary Similar to ubiquitin, SUMO forms chains, but the identity of SUMO-chain-modified factors and the purpose of this modification remain largely unknown. Here, we identify the budding yeast SUMO protease Ulp2, able to disassemble SUMO chains, as a DDK interactor enriched at replication origins that promotes DNA replication initiation. Replication-engaged DDK is SUMOylated on chromatin, becoming a degradation-prone substrate when Ulp2 no longer protects it against SUMO chain assembly. Specifically, SUMO chains channel DDK for SUMO-targeted ubiquitin ligase Slx5/Slx8-mediated and Cdc48 segregase-assisted proteasomal degradation. Importantly, the SUMOylation-defective ddk-KR mutant rescues inefficient replication onset and MCM activation in cells lacking Ulp2, suggesting that SUMO chains time DDK degradation. Using two unbiased proteomic approaches, we further identify subunits of the MCM helicase and other factors as SUMO-chain-modified degradation-prone substrates of Ulp2 and Slx5/Slx8. We thus propose SUMO-chain/Ulp2-protease-regulated proteasomal degradation as a mechanism that times the availability of functionally engaged SUMO-modified protein pools during replication and beyond. Graphical Abstract Highlights • Chromatin-bound DDK engaged in replication is SUMOylated at multiple sites • SUMO chains target DDK for STUbL-mediated Cdc48-assisted proteasomal degradation • SUMO protease Ulp2 protects DDK from degradation, allowing early steps of replication • Ulp2 curbs SUMO chain assembly, thus timing protein turnover in replication and beyond Psakhye et al. uncover that SUMO chains specifically counteracted by the Ulp2 SUMO protease function like a countdown timer when they are assembled on substrates of the Slx5/Slx8 SUMO-targeted ubiquitin ligase (STUbL), which channels them for proteasomal degradation, as demonstrated here for SUMOylated DDK engaged in DNA replication initiation. |
| Databáze: | OpenAIRE |
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