Structure and Specificity of the Vertebrate Anti-Mutator Uracil-DNA Glycosylase SMUG1
Biology (HMC), Chemistry (HMC)
Cytosine deamination is a major promutagenic process, generating G:U mismatches that can cause transition mutations if not repaired. Uracil is also introduced into DNA via nonmutagenic incorporation of dUTP during replication. In bacteria, uracil is excised by uracil-DNA glycosylases (UDG) related to E. coli UNG, and UNG homologs are found in mammals and viruses. Ung knockout mice display no increase in mutation frequency due to a second UDG activity, SMUG1, which is specialized for antimutational uracil excision in mammalian cells. Remarkably, SMUG1 also excises the oxidation-damage product 5-hydroxymethyluracil (HmU), but like UNG is inactive against thymine (5-methyluracil), a chemical substructure of HmU. We have solved the crystal structure of SMUG1 complexed with DNA and base-excision products. This structure indicates a more invasive interaction with dsDNA than observed with other UDGs and reveals an elegant water displacement/replacement mechanism that allows SMUG1 to exclude thymine from its active site while accepting HmU.
© 2003 Cell Press. All rights reserved.
Jane E.A. Wibley, Timothy R. Waters, Karl Haushalter, Gregory L. Verdine, Laurence H. Pearl, Structure and Specificity of the Vertebrate Anti-Mutator Uracil-DNA Glycosylase SMUG1, Molecular Cell, Volume 11, Issue 6, June 2003, Pages 1647-1659, ISSN 1097-2765, http://dx.doi.org/10.1016/S1097-2765(03)00235-1. (http://www.sciencedirect.com/science/article/pii/S1097276503002351)