Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 25, Pages 15526-15537Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.618132
Keywords
deubiquitylation (deubiquitination); DNA damage response; proteasome; RING finger protein 4 (RNF4); small ubiquitin-like modifier (SUMO); sumoylation; ubiquitin; ubiquitin-dependent protease; ubiquitylation (ubiquitination); USP11
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Funding
- Netherlands Organization for Scientific Research (NWO)
- ZonMW
- European Research Council
- Danish Research Council
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Background: RNF4 is a ubiquitin ligase targeted to SUMOylated proteins. Results: USP11 co-purified with RNF4 and can remove ubiquitin polymers attached to SUMO chains. Conclusion: USP11 is a ubiquitin protease with the ability to counteract RNF4 in the DNA damage response. Significance: Identification of a ubiquitin protease to balance the activity of a SUMO-targeted ubiquitin ligase. 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.
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