APOBEC3B (A3B)-catalyzed DNA cytosine deamination contributes to the overall mutational landscape in breast cancer. Molecular mechanisms responsible for A3B upregulation in cancer are poorly understood. Here we show that a single E2F cis-element mediates repression in normal cells and that expression is activated by its mutational disruption in a reporter construct or the endogenous A3B gene. The same E2F site is required for A3B induction by polyomavirus T antigen indicating a shared molecular mechanism. Proteomic and biochemical experiments demonstrate the binding of wildtype but not mutant E2F promoters by repressive PRC1.6/E2F6 and DREAM/E2F4 complexes. Knockdown and overexpression studies confirm the involvement of these repressive complexes in regulating A3B expression. Altogether, these studies demonstrate that A3B expression is suppressed in normal cells by repressive E2F complexes and that viral or mutational disruption of this regulatory network triggers overexpression in breast cancer and provides fuel for tumor evolution.

中文翻译：

---

表征 RB/E2F 通路控制癌症基因组 DNA 脱氨酶 APOBEC3B 表达的机制

APOBEC3B (A3B) 催化的 DNA 胞嘧啶脱氨基作用有助于乳腺癌的整体突变格局。负责癌症中 A3B 上调的分子机制知之甚少。在这里，我们展示了单个 E2F 顺式元件介导了正常细胞中的抑制，并且该表达被其在报告基因构建体或内源性 A3B 基因中的突变破坏激活。多瘤病毒 T 抗原诱导 A3B 需要相同的 E2F 位点，表明有共同的分子机制。蛋白质组学和生化实验证明了抑制性 PRC1.6/E2F6 和 DREAM/E2F4 复合物与野生型而非突变型 E2F 启动子的结合。击倒和过表达研究证实了这些抑制性复合物参与调节 A3B 表达。共，