Uracil-DNA Glycosylase (UNG)-Deficient Mice Reveal a Primary Role of the Enzyme during DNA Replication

• Published in: Molecular cell 2000-06, Vol.5 (6), p.1059-1065
• Main Authors: Nilsen, Hilde, Rosewell, Ian, Robins, Peter, Skjelbred, Camilla F, Andersen, Sonja, Slupphaug, Geir, Daly, Graham, Krokan, Hans E, Lindahl, Tomas, Barnes, Deborah E
• Format: Article
• Language: English
• Subjects: Animals; Cell Nucleus - enzymology; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cells, Cultured; Cytosine - metabolism; Deoxyuracil Nucleotides - metabolism; DNA - biosynthesis; DNA - genetics; DNA - metabolism; DNA Glycosylases; DNA Repair - genetics; DNA Replication; Female; Gene Deletion; Kinetics; Male; Mice; Mice, Knockout; Mutagenesis - genetics; N-Glycosyl Hydrolases - deficiency; N-Glycosyl Hydrolases - genetics; N-Glycosyl Hydrolases - metabolism; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; UNG protein; Uracil - metabolism; Uracil-DNA Glycosidase; uracil-DNA glycosylase
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/S1097-2765(00)80271-3

Gene-targeted knockout mice have been generated lacking the major uracil-DNA glycosylase, UNG. In contrast to ung − mutants of bacteria and yeast, such mice do not exhibit a greatly increased spontaneous mutation frequency. However, there is only slow removal of uracil from misincorporated dUMP in isolated ung −/− nuclei and an elevated steady-state level of uracil in DNA in dividing ung −/− cells. A backup uracil-excising activity in tissue extracts from ung null mice, with properties indistinguishable from the mammalian SMUG1 DNA glycosylase, may account for the repair of premutagenic U:G mispairs resulting from cytosine deamination in vivo. The nuclear UNG protein has apparently evolved a specialized role in mammalian cells counteracting U:A base pairs formed by use of dUTP during DNA synthesis.