USP7 and VCPFAF1 define the SUMO/Ubiquitin landscape at the DNA replication fork
| Autor: | Emilio Lecona, Patricia Ubieto-Capella, André Franz, Domenic Pilger, Thorsten Hoppe, Antonio Galarreta, Fabian den Brave, Pablo Valledor, Guillermo de la Vega-Barranco, Alejandro Fernández-Llorente, Vanesa Lafarga, Oscar Fernandez-Capetillo |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
DNA Replication
ATPase DUB Article General Biochemistry Genetics and Molecular Biology Cofactor Animals Genetically Modified Evolution Molecular Ubiquitin-Specific Peptidase 7 Ubiquitin Valosin Containing Protein ubiquitin Endopeptidases Animals Humans UBXN-3 Caenorhabditis elegans Caenorhabditis elegans Proteins FAF1 Adaptor Proteins Signal Transducing MATH-33 biology DNA synthesis Chemistry Ubiquitination DNA replication Sumoylation HCT116 Cells DNA Replication Fork biology.organism_classification Chromatin Cell biology CDC-48 SUMO USP7 MCF-7 Cells biology.protein Apoptosis Regulatory Proteins Carrier Proteins VCP HeLa Cells |
| Zdroj: | Cell Reports |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2021.109819 |
| Popis: | Summary The AAA+ ATPase VCP regulates the extraction of SUMO and ubiquitin-modified DNA replication factors from chromatin. We have previously described that active DNA synthesis is associated with a SUMO-high/ubiquitin-low environment governed by the deubiquitylase USP7. Here, we unveil a functional cooperation between USP7 and VCP in DNA replication, which is conserved from Caenorhabditis elegans to mammals. The role of VCP in chromatin is defined by its cofactor FAF1, which facilitates the extraction of SUMOylated and ubiquitylated proteins that accumulate after the block of DNA replication in the absence of USP7. The inactivation of USP7 and FAF1 is synthetically lethal both in C. elegans and mammalian cells. In addition, USP7 and VCP inhibitors display synergistic toxicity supporting a functional link between deubiquitylation and extraction of chromatin-bound proteins. Our results suggest that USP7 and VCPFAF1 facilitate DNA replication by controlling the balance of SUMO/Ubiquitin-modified DNA replication factors on chromatin. Graphical abstract Highlights • VCP and USP7 control the SUMO/ubiquitin landscape during DNA replication • VCP is recruited by FAF1 to chromatin-associated SUMO/ubiquitylated proteins • FAF1 recognizes both SUMO and ubiquitin on target proteins • The control of DNA replication by VCPFAF1 and USP7 is evolutionarily conserved Chromatin at DNA replication forks is SUMO-rich and ubiquitin-poor. Franz et al. report that FAF1 is a dual reader of SUMO and ubiquitin targeting VCP to extract DNA replication factors from chromatin in C. elegans and human cells. Together with USP7, VCPFAF1 controls the SUMO/ubiquitin landscape during replication. |
| Databáze: | OpenAIRE |
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