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Structural basis for uracil removal from DNA by human SMUG1

Ludäscher, Julian M. ; Scaletti Hutchinson, Emma ; Vila-Julià, Guillem ; Jemth, Ann Sofie ; Shahid, Saher ; Wiita, Elisee ; Cabeza de Vaca, Israel ; Pach, Szymon ; Gajdos, Lukas and Aggarwal, Swati LU , et al. (2026) In Nature Communications 17(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
17
issue
1
article number
4809
publisher
Nature Publishing Group
external identifiers
  • pmid:42230560
  • scopus:105040747162
ISSN
2041-1723
DOI
10.1038/s41467-026-72937-0
language
English
LU publication?
yes
id
28c260a2-9e98-49e8-8ebd-51cd6b3e44f7
date added to LUP
2026-07-01 11:42:59
date last changed
2026-07-02 03:00:07
@article{28c260a2-9e98-49e8-8ebd-51cd6b3e44f7,
  abstract     = {{<p>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.</p>}},
  author       = {{Ludäscher, Julian M. and Scaletti Hutchinson, Emma and Vila-Julià, Guillem and Jemth, Ann Sofie and Shahid, Saher and Wiita, Elisee and Cabeza de Vaca, Israel and Pach, Szymon and Gajdos, Lukas and Aggarwal, Swati and Walse, Ellen and Mortusewicz, Oliver and Helleday, Thomas and Carlsson, Jens and Stenmark, Pål}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Structural basis for uracil removal from DNA by human SMUG1}},
  url          = {{http://dx.doi.org/10.1038/s41467-026-72937-0}},
  doi          = {{10.1038/s41467-026-72937-0}},
  volume       = {{17}},
  year         = {{2026}},
}