Certain mutagens, including the APOBEC3 (A3) cytosine deaminase enzymes, can create multiple genetic changes in a single event. Activity of A3s results in striking ‘mutation showers’ occurring near DNA breakpoints; however, less is known about the mechanisms underlying the majority of A3 mutations. We classified the diverse patterns of clustered mutagenesis in tumor genomes, which identified a new A3 pattern: nonrecurrent, diffuse hypermutation (omikli). This mechanism occurs independently of the known focal hypermutation (kataegis), and is associated with activity of the DNA mismatch-repair pathway, which can provide the single-stranded DNA substrate needed by A3, and contributes to a substantial proportion of A3 mutations genome wide. Because mismatch repair is directed towards early-replicating, gene-rich chromosomal domains, A3 mutagenesis has a high propensity to generate impactful mutations, which exceeds that of other common carcinogens such as tobacco smoke and ultraviolet exposure. Cells direct their DNA repair capacity towards more important genomic regions; thus, carcinogens that subvert DNA repair can be remarkably potent.

某些诱变剂，包括APOBEC3（A3）胞嘧啶脱氨酶，可以在单个事件中产生多种遗传变化。A3的活性导致在DNA断裂点附近发生惊人的“突变阵雨”。但是，对于大多数A3突变的潜在机制了解甚少。我们对肿瘤基因组中聚集诱变的不同模式进行了分类，从而确定了一种新的A3模式：非复发性，弥漫性超突变（omikli）。该机制独立于已知的局灶性超突变（kataegis）发生，并且与DNA错配修复途径的活性有关，后者可以提供A3所需的单链DNA底物，并在整个基因组范围内对A3突变产生很大的影响。由于错配修复是针对早期复制的，富含基因的染色体结构域，A3诱变很容易产生有影响的突变，超过了其他常见的致癌物，例如烟草烟雾和紫外线照射。细胞将其DNA修复能力导向更重要的基因组区域。因此，破坏DNA修复的致癌物可能非常有效。