Ludäscher, J.M. orcid.org/0009-0005-7242-5133, Scaletti Hutchinson, E., Vila-Julià, G. orcid.org/0000-0001-5576-7442 et al. (12 more authors) (2026) Structural basis for uracil removal from DNA by human SMUG1. Nature Communications, 17 (1). 4809. ISSN: 2041-1723
Abstract
Human single-strand-selective monofunctional uracil DNA glycosylase 1 (hSMUG1) removes uracil, 5-hydroxymethyluracil (5hmU) and 5-fluorouracil (5FU) from DNA, thereby initiating the base excision repair (BER) process. hSMUG1 is important for maintaining genomic integrity and plays a significant role in cancer biology. Here, we present the structures of hSMUG1, including complexes with products (uracil and 5FU) and an enzyme-product complex of hSMUG1 with double-stranded DNA (dsDNA). Analysis of our hSMUG1-dsDNA complex reveals how uracil is flipped out of the dsDNA for excision and identifies key residues that we confirm to be critical for both DNA binding and enzymatic activity. Furthermore, our hSMUG1 substrate complexes, molecular dynamics simulations and neutron diffraction data suggest a mechanism by which the substrate uracil rotates following base excision. The structural and functional information presented here will be highly useful for the future development of inhibitors and/or activators targeting hSMUG1.
Metadata
| Item Type: | Article |
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| Authors/Creators: |
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| Copyright, Publisher and Additional Information: | © 2026 The authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. 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/4.0/. |
| Keywords: | Uracil; Humans; Uracil-DNA Glycosidase; DNA; Excision Repair; Molecular Dynamics Simulation; Fluorouracil; Pentoxyl; Crystallography, X-Ray; DNA Repair; Protein Binding |
| Dates: |
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| Institution: | The University of Sheffield |
| Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
| Date Deposited: | 13 Jul 2026 14:08 |
| Last Modified: | 15 Jul 2026 09:02 |
| Status: | Published |
| Publisher: | Springer Science and Business Media LLC |
| Refereed: | Yes |
| Identification Number: | 10.1038/s41467-026-72937-0 |
| Related URLs: | |
| Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:243058 |
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