RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response

• Published in: The Journal of cell biology 2013-06, Vol.201 (6), p.797-807
• Main Authors: Poulsen, Sara L, Hansen, Rebecca K, Wagner, Sebastian A, van Cuijk, Loes, van Belle, Gijsbert J, Streicher, Werner, Wikström, Mats, Choudhary, Chunaram, Houtsmuller, Adriaan B, Marteijn, Jurgen A, Bekker-Jensen, Simon, Mailand, Niels
• Format: Article
• Language: English
• Subjects: Cell Line, Transformed; Cells; DNA damage; DNA Damage - physiology; DNA Repair - physiology; HeLa Cells; Humans; Ligases - genetics; Ligases - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Plasmids - genetics; Proteins; RNA, Small Interfering - genetics; Signal Transduction - physiology; Signal Transduction - radiation effects; Small Ubiquitin-Related Modifier Proteins - genetics; Small Ubiquitin-Related Modifier Proteins - metabolism; Sumoylation - physiology; Sumoylation - radiation effects; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - physiology; Ubiquitination - radiation effects; Ubiquitins - genetics; Ubiquitins - metabolism; Ultraviolet radiation; Ultraviolet Rays - adverse effects
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201212075

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.