Molecular basis for the regulation of the SUMOylation activity of the Smc5/6 complex by Esc2

Abstract

Post-translational modification by SUMO regulates a wide array of cellular processes. Despite the large number of SUMOylated substrates, only a limited set of SUMO E3 ligases have been identified, raising important questions about how substrate specificity is achieved. In budding yeast, the nuclear protein Esc2 functions as a cofactor in the SUMO pathway through its interaction with the E2 enzyme Ubc9. Esc2 is relevant under conditions of replicative stress, promoting the removal of recombination intermediates during DNA replication. This role has been largely attributed to its ability to enhance the SUMO E3 ligase activity of Nse2, a subunit of the Smc5/6 complex. Here, we uncover the molecular mechanism underlying Esc2-mediated stimulation of Nse2-dependent SUMOylation by identifying a direct interaction between the C-terminal SUMO-interacting motif of Nse2 and the Esc2 SLD2 domain. These coordinated interactions facilitate the formation of a productive E3-E2~SUMO complex and promote efficient SUMO transfer to substrates such as Sgs1 and Top3, thereby enhancing the processing of recombination intermediates and contributing to genome integrity.

Metadata

Item Type:	Article
Authors/Creators:	Borràs-Gas, H. https://orcid.org/0000-0002-3633-9132 Solé-Soler, R. https://orcid.org/0000-0002-1622-3351 do Aido-Machado, R. https://orcid.org/0000-0001-6331-4216 Matas, M. Williamson, M.P. https://orcid.org/0000-0001-5572-1903 Varejão, N. https://orcid.org/0000-0002-6952-8896 Torres-Rosell, J. Reverter, D. https://orcid.org/0000-0002-5347-0992
Copyright, Publisher and Additional Information:	© The Author(s) 2026. Open Access: This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Keywords:	Biochemistry and Cell Biology; Biological Sciences; Genetics; Biotechnology; Normal biological development and functioning; Generic health relevance
Dates:	Accepted: 10 August 2026 Published (online): 24 August 2026 Published: 24 August 2026
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield)
Funding Information:	Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/R000727/1
Date Deposited:	08 Sep 2026 08:48
Last Modified:	08 Sep 2026 08:48
Status:	Published online
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s42003-026-10806-8
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:245211

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Molecular basis for the regulation of the SUMOylation activity of the Smc5/6 complex by Esc2

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