Excision of deaminated cytosine from the vertebrate genome: role of the SMUG1 uracil-DNA glycosylase

Gene-targeted mice deficient in the evolutionarily conserved uracil-DNA gly cosylase encoded by the UNG gene surprisingly lack the mutator phenotype ch aracteristic 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 a s the major uracil-DNA glycosylase in UNG-deficient mice. SMUG1 is present at similar levels in cell nuclei of non-proliferating and proliferating tis sues, indicating a replication-independent role in DNA repair. The SMUG1 en zyme 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 bei ng largely localized to replication foci in mammalian cells to counteract d e novo dUMP incorporation into DNA.