Abstract: Recently, using whole-genome sequencing data of breast cancer genomes we revealed localized regions of dense somatic hypermutation, called kataegis, in which substitutions at C:G base pairs occurring within a distinctive sequence context were found associated with clusters of genomic rearrangements. The mechanism of kataegis is unknown. On the basis of similarities in mutation class and sequence context in experimental systems, members of the AID/APOBEC family of cytidine deaminases were implicated. Here we expressed members of this gene family in yeast and demonstrate that mutation clusters mimicking many of the features of kataegis in cancer, can be generated. Because the genomic location of each stretch of kataegis is different between individual human cancer genomes, it was reasoned that kataegis is triggered by a local stochastic event, such as a DNA double strand break. Here, we have introduced double strand breaks into the yeast genome and shown that kataegis is elicited in its vicinity. Furthermore, kataegis is substantially diminished in the absence of uracil-DNA glycosylase, indicating that base excision DNA repair is implicated in its genesis. Additionally, the mutation sequence context preferences revealed by these yeast experiments suggest that APOBEC3B and APOBEC3A are the deaminases most likely responsible for the kataegis observed in human cancer. The results therefore provide insights into the mechanism of kataegis and indicate a contribution of APOBEC3B/A-catalyzed DNA deamination to genome mutation in cancer. Finally, we show using an algorithm developed to allow efficient detection of kataegis in other publicly available whole-genome sequenced datasests that this phenomenon is not restricted to breast cancer.