Model for APOBEC3B mutagenesis in cancer. The central pathway goes left to right and then circles back to depict error-free base excision repair of two C-to-U lesions catalyzed by APOBEC3B (A3B). Most genomic uracils are probably repaired in this manner. However, intermediates in this repair process can lead to a variety of mutagenic outcomes. Top left: C-to-T mutations can result from DNA synthesis over uracilated templates (as in Figure 2) or from synthesis over an abasic site because most DNA polymerases insert deoxy-adenosine opposite this non-instructional lesion. Bottom left: C-to-G transversions most likely occur when REV1 inserts deoxy-cytidine opposite an abasic site followed by repair of the original lesion or a round of DNA synthesis. Top right: a single-stranded DNA break (SSB) can result from cleavage of the phosphodiester backbone by APEX (normal component of BER). Bottom right: A double-stranded DNA break (DSB) can result from opposing APEX-mediated endonucleolytic cleavages, or from a DNA replication fork hitting a single-stranded break. Both single- and double-stranded breaks can lead to additional mutagenic outcomes such as kataegis (A3B-catalyzed deamination of exposed single-stranded DNA) and insertions, deletions, amplifications, inversions, and translocations. LIG, DNA ligase; POL, polymerase; UDG, uracil DNA glycosylase.