Uracil in DNA--occurrence, consequences and repair.

Uracil in DNA results from deamination of cytosine, resulting in mutagenic U : G mispairs, and misincorporation of dUMP, which gives a less harmful U : A pair. At least four different human DNA glycosylases may remove uracil and thus generate an abasic site, which is itself cytotoxic and potentially mutagenic. These enzymes are UNG, SMUG1, TDG and MBD4. The base excision repair process is completed either by a short patch- or long patch pathway, which largely use different proteins. UNG2 is a major nuclear uracil-DNA glycosylase central in removal of misincorporated dUMP in replication foci, but recent evidence also indicates an important role in repair of U : G mispairs and possibly U in single-stranded DNA. SMUG1 has broader specificity than UNG2 and may serve as a relatively efficient backup for UNG in repair of U : G mismatches and single-stranded DNA. TDG and MBD4 may have specialized roles in the repair of U and T in mismatches in CpG contexts. Recently, a role for UNG2, together with activation induced deaminase (AID) which generates uracil, has been demonstrated in immunoglobulin diversification. Studies are now underway to examine whether mice deficient in Ung develop lymphoproliferative malignancies and have a different life span.