APOBEC3B: Pathological consequences of an innate immune DNA mutator

Cancer is a disease that results from alterations in the cellular genome. Several recent studies have identified mutational signatures that implicate a variety of mutagenic processes in cancer, a major one of which is explained by the enzymatic activity of the DNA cytosine de-aminase, APOBEC3B. As a deaminase, APOBEC3B converts cytosines to uracils in single-stranded DNA. Failure to properly repair these uracil lesions can result in a diverse array of mutations. For instance, DNA uracils can template the insertion of complementary adenines leading to C-to-T transition mutations. DNA uracils can also be converted into abasic sites that, depending upon the DNA polymerase recruited to by-pass this lesion in the template strand, can lead to adenine insertion and C-to-T mutations as well as cytosine insertion and C-to-G transversion mutations. Finally, DNA uracils can also be converted into DNA breaks that may precipitate some types of larger chromosomal aberrations observed in cancer. These stud-ies cumulatively demonstrate that APOBEC3B is a major source of genetic heterogeneity in several human cancers and, as such, this enzyme may prove to be a critical diagnostic and therapeutic target.