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While most SUMO E3s fulfill their roles as single proteins, the conserved Nse2 E3 is an obligatory subunit of the genome-protecting complex Smc5\/6. How the Smc5\/6 complex functions in SUMOylation and the roles of its non-SUMO E3 subunits in this process remain to be elucidated. Here we examine the budding yeast Smc5\/6 in SUMOylation reactions and in cellular SUMOylation assays. Biochemical data show that DNA stimulates Smc5\/6\u2019s E3 activity by fostering enzyme and substrate proximity. Mutational analyses reveal that four non-SUMO E3 subunits utilize their DNA-binding abilities to support this stimulation. Moreover, ATP binding by SMC subunits favors SUMOylation by enhancing Smc5\/6 association with DNA and chromatin and by enabling conformational changes. Our findings thus provide evidence for a specialized DNA- and ATP-stimulated composite SUMO E3 complex that uses inter-subunit collaboration to achieve efficient SUMOylation in genome regulation.<\/jats:p>","DOI":"10.1038\/s41467-026-75592-7","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T07:56:26Z","timestamp":1784793386000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-subunit collaboration enables Smc5\/6 to function as a composite SUMO E3 complex"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9654-6566","authenticated-orcid":false,"given":"Xiaoyu","family":"Xue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4317-8330","authenticated-orcid":false,"given":"Jiayi","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9293-6006","authenticated-orcid":false,"given":"Shibai","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofya","family":"Ignatyeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Gallegos-Elias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"McEntire-Benitez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinji","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanu Rani","family":"Kar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Epps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4364-8075","authenticated-orcid":false,"given":"Lillian","family":"Eliaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiana","family":"Holland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8302-6905","authenticated-orcid":false,"given":"Xiaolan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"75592_CR1","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1038\/s41580-022-00500-y","volume":"23","author":"ACO Vertegaal","year":"2022","unstructured":"Vertegaal, A. 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