title: Ubiquitin-specific Protease 11 (USP11) Deubiquitinates Hybrid Small Ubiquitin-like Modifier (SUMO)-Ubiquitin Chains to Counteract RING Finger Protein 4 (RNF4).
abstract: Ring finger protein 4 (RNF4) is a SUMO-targeted ubiquitin E3 ligase with a pivotal function in the DNA damage response (DDR). SUMO interaction motifs (SIMs) in the N-terminal part of RNF4 tightly bind to SUMO polymers, and RNF4 can ubiquitinate these polymers in vitro. Using a proteomic approach, we identified the deubiquitinating enzyme ubiquitin-specific protease 11 (USP11), a known DDR-component, as a functional interactor of RNF4. USP11 can deubiquitinate hybrid SUMO-ubiquitin chains to counteract RNF4. SUMO-enriched nuclear bodies are stabilized by USP11, which functions downstream of RNF4 as a counterbalancing factor. In response to DNA damage induced by methyl methanesulfonate, USP11 could counteract RNF4 to inhibit the dissolution of nuclear bodies. Thus, we provide novel insight into cross-talk between ubiquitin and SUMO and uncover USP11 and RNF4 as a balanced SUMO-targeted ubiquitin ligase/protease pair with a role in the DDR.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Ivo A
authors.initials: IA
authors.lastname: Hendriks
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Schimmel
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Karolin
authors.initials: K
authors.lastname: Eifler
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. Electronic address: vertegaal@lumc.nl.
authors.forename: Alfred C O
authors.initials: ACO
authors.lastname: Vertegaal
mesh_terms: D020816:Amino Acid Motifs; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; C114070:RNF4 protein, human; D025842:SUMO-1 Protein; D014157:Transcription Factors; C101359:USP11 protein, human; D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases; D013869:Thiolester Hydrolases
keywords: DNA damage response; RING finger protein 4 (RNF4); USP11; deubiquitylation (deubiquitination); proteasome; small ubiquitin-like modifier (SUMO); sumoylation; ubiquitin; ubiquitin-dependent protease; ubiquitylation (ubiquitination)