title: Excision of deaminated cytosine from the vertebrate genome: role of the SMUG1 uracil-DNA glycosylase.
abstract: Gene-targeted mice deficient in the evolutionarily conserved uracil-DNA glycosylase encoded by the UNG gene surprisingly lack the mutator phenotype characteristic of bacterial and yeast ung(-) mutants. A complementary uracil-DNA glycosylase activity detected in ung(-/-) murine cells and tissues may be responsible for the repair of deaminated cytosine residues in vivo. Here, specific neutralizing antibodies were used to identify the SMUG1 enzyme as the major uracil-DNA glycosylase in UNG-deficient mice. SMUG1 is present at similar levels in cell nuclei of non-proliferating and proliferating tissues, indicating a replication- independent role in DNA repair. The SMUG1 enzyme is found in vertebrates and insects, whereas it is absent in nematodes, plants and fungi. We propose a model in which SMUG1 has evolved in higher eukaryotes as an anti-mutator distinct from the UNG enzyme, the latter being largely localized to replication foci in mammalian cells to counteract de novo dUMP incorporation into DNA.
authors.affiliation: Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, EN6 3LD, UK.
authors.forename: H
authors.initials: H
authors.lastname: Nilsen
authors.forename: K A
authors.initials: KA
authors.lastname: Haushalter
authors.forename: P
authors.initials: P
authors.lastname: Robins
authors.forename: D E
authors.initials: DE
authors.lastname: Barnes
authors.forename: G L
authors.initials: GL
authors.lastname: Verdine
authors.forename: T
authors.initials: T
authors.lastname: Lindahl
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000918:Antibody Specificity; D020137:Base Pair Mismatch; D002455:Cell Division; D003596:Cytosine / Q000378:metabolism*; D043525:Cytosine Deaminase; D004249:DNA Damage; D045647:DNA Glycosylases; D004260:DNA Repair; D019143:Evolution, Molecular; D016678:Genome; D006147:Guanine; D006801:Humans; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D009699:N-Glycosyl Hydrolases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009700:Nucleoside Deaminases / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014498:Uracil; D051981:Uracil-DNA Glycosidase; D014714:Vertebrates / Q000235:genetics
chemical_list: D000906:Antibodies; D014498:Uracil; D006147:Guanine; D003596:Cytosine; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C498095:SMUG1 protein, human; D051981:Uracil-DNA Glycosidase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase