Researchers have captured the first atomic structures of human SMUG1, an enzyme that helps cells repair damaged DNA. The findings provide new insight into how cells recognise and remove harmful DNA bases, and may support future efforts to develop drugs that target this DNA repair pathway.
"These structures give us the first detailed view of how human SMUG1 engages damaged DNA and carries out the first steps of repair," says professor Pål Stenmark, who led the study.
DNA is constantly damaged by normal processes in our cells, as well as by environmental factors and cancer treatments. If the damage is not repaired, it can lead to permanent mutations. One enzyme involved in this repair process is human SMUG1, which removes uracil and related damaged bases from DNA. Uracil is one of the four nucleotide bases normally found in the nucleic acid RNA, but when it appears in DNA it can cause problems if not repaired.
Until now, researchers have not had a detailed three-dimensional picture of human SMUG1. In the new study, published in Nature Communications, they present the first structures of the enzyme. These structures show SMUG1 in different states: on its own, bound to the molecules uracil and 5-fluorouracil, and attached to double-stranded DNA.
Linked to cancer biology
The molecule 5-fluorouracil is a cytostatic agent widely used in cancer treatment. After it has been incorporated into our DNA, SMUG1 acts to remove it. Because SMUG1 activity is connected to both DNA repair and cancer biology, the new structures provide a foundation for future efforts to design drugs that specifically target the enzyme.
The study also report the first joint neutron and X-ray structure of a DNA-binding protein.
"This provides rare insight into proton positions and hydrogen-bonding networks in the enzyme active site, details that are often difficult to resolve with X-ray crystallography alone," says professor Pål Stenmark.
The work is a collaboration between Uppsala University, Karolinska Institutet, Institut Laue-Langevin (ILL), European Spallation Source (ESS) and Stockholm University.
"The finding is especially timely for Sweden, as the European Spallation Source (ESS), the world's most powerful neutron source is currently being built in Sweden, this will dramatically expand opportunities for studies of this kind," says Pål Stenmark.
Together, the findings give researchers a detailed picture of how SMUG1 repairs damaged DNA. They will also support efforts to develop drugs that target this DNA repair pathway.
About the study
The article Structural basis for uracil removal from DNA by human SMUG1 is published in Nature Communications.
DOI: 10.1038/s41467-026-72937-0
