Structure and Specificity of the Vertebrate Anti-Mutator Uracil-DNA Glycosylase SMUG1

Authors

Jane E.A. Wibley, The Institute of Cancer Research
Timothy R. Waters, University of College London
Karl A. Haushalter, Harvey Mudd CollegeFollow
Gregory L. Verdine, Harvard University
Laurence H. Pearl, The Institute of Cancer Research

Document Type

Article

Department

Biology (HMC)

Publication Date

2003

Abstract

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.

Rights Information

© 2003 Cell Press. All rights reserved.

DOI

10.1016/S1097-2765(03)00235-1

Recommended Citation

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)