Chapter 10. Genomic Uracil in Biology, Immunity and Cancer

U–G mismatches in DNA generally result from spontaneous cytosine deamination and are repaired by the base excision repair pathway to avoid mutations. However, as part of the adaptive immune response in B cells U–G mismatches are enzymatically generated in the Ig genes by activation-induced cytidine deaminase. These uracils are further processed by the uracil–DNA glycosylase UNG and funneled into mutagenic pathways to generate point mutations and strand breaks resulting in somatic hypermutation and class shift recombination, respectively. Cytosine deamination by activation-induced cytidine deaminase and other DNA deaminases is also a significant source of mutations in cancer. Human DNA polymerases do not discriminate between dTTP and dUTP. Misincorporation of dUMP generates U–A pairs that are indirectly mutagenic through erroneous processing of abasic sites. Some cells have surprisingly high dUTP/dTTP ratios, suggesting that the incorporation of dUMP during DNA replication or repair may be considerable. Mammalian cells have four different uracil–DNA glycosylases; UNG, SMUG1, TDG and MBD4. These have in part complementary, but also distinct functions in base excision repair, immunity and epigenetic regulation. In addition, they may modify responses to fluoropyrimidines in cancer treatment.