cl00483

Uracil-DNA glycosylases (UDG) and related enzymes; Uracil-DNA glycosylases (UDG) catalyzes the removal of uracil from DNA, which initiates the DNA base excision repair pathway. Uracil in DNA can arise as a result of mis-incorporation of dUMP residues by DNA polymerase or via deamination of cytosine. Uracil in DNA mispaired with guanine is one of the major pro-mutagenic events, causing G:C->A:T mutations. Thus, UDG is an essential enzyme for maintaining the integrity of genetic information. At least five UDG families have been characterized so far; these families share similar overall folds and common active site motifs. They demonstrate different substrate specificities, but often the function of one enzyme can be complemented by the other. Family 1 enzymes are active against uracil in both ssDNA and dsDNA, and recognize uracil explicitly in an extrahelical conformation via a combination of protein and bound-water interactions. Family 2 enzymes are mismatch specific and explicitly recognize the widowed guanine on the complementary strand, rather than the extrahelical scissile pyrimidine. This allows a broader specificity so that some Family 2 enzymes can excise uracil as well as 3, N(4)-ethenocytosine from mismatches with guanine. A Family 3 UDG from human was first characterized to remove Uracil from ssDNA, hence the name hSMUG (single-strand-selective monofunctional uracil-DNA glycosylase). However, subsequent research has shown that hSMUG1 and its rat ortholog can remove uracil and its oxidized pyrimidine derivatives from both, ssDNA and dsDNA. Enzymes in Families 4 and 5 are both thermostable. Family 4 enzymes specifically recognize uracil in a manner similar to human UDG (Family 1), rather than guanine in the complementary strand DNA, as does E. coli MUG (Family 2). These results suggest that the mechanism by which Family 4 UDGs remove uracils from DNA is similar to that of Family 1 enzyme. Although Family 5 enzymes are close relatives of Family 4, they show different substrate specificities.