title: RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response.
abstract: Protein modifications by ubiquitin and small ubiquitin-like modifier (SUMO) play key roles in cellular signaling pathways. SUMO-targeted ubiquitin ligases (STUbLs) directly couple these modifications by selectively recognizing SUMOylated target proteins through SUMO-interacting motifs (SIMs), promoting their K48-linked ubiquitylation and degradation. Only a single mammalian STUbL, RNF4, has been identified. We show that human RNF111/Arkadia is a new STUbL, which used three adjacent SIMs for specific recognition of poly-SUMO2/3 chains, and used Ubc13-Mms2 as a cognate E2 enzyme to promote nonproteolytic, K63-linked ubiquitylation of SUMOylated target proteins. We demonstrate that RNF111 promoted ubiquitylation of SUMOylated XPC (xeroderma pigmentosum C) protein, a central DNA damage recognition factor in nucleotide excision repair (NER) extensively regulated by ultraviolet (UV)-induced SUMOylation and ubiquitylation. Moreover, we show that RNF111 facilitated NER by regulating the recruitment of XPC to UV-damaged DNA. Our findings establish RNF111 as a new STUbL that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response.
authors.affiliation: Ubiquitin Signaling Group, Department of Disease Biology, The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Poulsen
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Hansen
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Wagner
authors.forename: Loes
authors.initials: L
authors.lastname: van Cuijk
authors.forename: Gijsbert J
authors.initials: GJ
authors.lastname: van Belle
authors.forename: Werner
authors.initials: W
authors.lastname: Streicher
authors.forename: Mats
authors.initials: M
authors.lastname: Wikström
authors.forename: Chunaram
authors.initials: C
authors.lastname: Choudhary
authors.forename: Adriaan B
authors.initials: AB
authors.lastname: Houtsmuller
authors.forename: Jurgen A
authors.initials: JA
authors.lastname: Marteijn
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.forename: Niels
authors.initials: N
authors.lastname: Mailand
mesh_terms: D002461:Cell Line, Transformed; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000502:physiology* / Q000528:radiation effects; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology / Q000528:radiation effects; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014452:Ubiquitins; C471607:UBE2N protein, human; C114715:UBE2V2 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C486067:RNF111 protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases