title: USP7 is a SUMO deubiquitinase essential for DNA replication.
abstract: Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates DNA replication. We have previously shown that chromatin around replisomes is rich in SUMO and poor in Ub, whereas mature chromatin exhibits an opposite pattern. How this SUMO-rich, Ub-poor environment is maintained at sites of DNA replication in mammalian cells remains unexplored. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination. Inhibition or genetic deletion of USP7 leads to the accumulation of Ub on SUMOylated proteins, which are displaced away from replisomes. Our findings provide a model explaining the differential accumulation of SUMO and Ub at replication forks and identify an essential role of USP7 in DNA replication that should be considered in the development of USP7 inhibitors as anticancer agents.
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Lecona
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Rodriguez-Acebes
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Specks
authors.affiliation: Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Lopez-Contreras
authors.affiliation: Proteomics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ruppen
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.affiliation: Proteomics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Muñoz
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Mendez
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
mesh_terms: D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D025841:Small Ubiquitin-Related Modifier Proteins / Q000032:analysis / Q000378:metabolism*; D058207:Sumoylation; D043222:Ubiquitin Thiolesterase / Q000032:analysis / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases / Q000032:analysis / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases