PERSPECTIVE Mutagenesis by AID: Being in the Right Place at the Right Time

Deamination of cytosine is a common consequence of the natural hydrolytic decay of DNA. However, it is also part of a mutagenesis programme in immune cells, initiated by activation-induced cytidine deaminase (AID) acting on the genes that encode antibodies. Cytosine deami-nation by AID results in a staggering number of localised point mutations. This is achieved within a few cell divisions despite the rather innocuous nature of base change in the DNA, deoxy-uracil, which is efficiently removed by the uracil-DNA glycosylase (UNG). Highly abun-dant during S phase, the main role of UNG is to remove uracil misincorporated during DNA replication, but it can act at other times, both on double and single stranded DNA (dsDNA and ssDNA, respectively). Cells have a back up glycosylase, SMUG1 [1], that removes uracil from double stranded DNA, a pathway ideally suited to faithfully repair deaminated cytosines out-side replication. It has been quite a mystery why repair of uracils induced by AID is mostly mutagenic; a favoured hypothesis was that uracil excision at the wrong time during the cell cycle would prevent faithful repair. The work by Le and Maizels [2] on this issue goes some way to resolving this question. AID is a powerful mutator of single stranded DNA in B cells. Its activity can be misdirecte