APOBEC3B is an enzymatic source of mutation in breast cancer.
APOBEC3B is an enzymatic source of mutation in breast cancer.
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癌症的发展需要多种突变，基因组测序表明，包括乳腺癌在内的多种癌症的体细胞突变谱以C-T转变为主。大多数这些突变发生在整个基因组中不利于水解的非甲基化胞嘧啶处，并且有时呈簇状。在这里，我们证明 DNA 胞嘧啶脱氨酶 APOBEC3B (A3B) 可能是这些突变的来源。 A3B mRNA 在大多数原发性乳腺肿瘤和乳腺癌细胞系中上调。表达高水平 A3B 的肿瘤的突变数量是表达低水平的肿瘤的两倍，并且更有可能发生 TP53 突变。内源性 A3B 蛋白主要存在于细胞核中，是乳腺癌细胞系提取物中唯一可检测到的 DNA C-to-U 编辑活性来源。敲低实验表明，内源性 A3B 与基因组尿嘧啶水平升高、突变频率增加以及 C 到 T 转变相关。此外，诱导的 A3B 过度表达会导致细胞周期偏差、细胞死亡、DNA 断裂、γ-H2AX 积累和 C 到 T 突变。我们的数据提出了一个模型，其中 A3B 催化的脱氨作用提供了乳腺癌中 DNA 损伤的慢性来源，该来源可以选择 TP53 失活并解释一些肿瘤如何快速进化并表现出异质性。
Multiple mutations are required for cancer development, and genome sequencing has revealed that several cancers, including breast, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavored non-methylated cytosines throughout the genome, and are sometimes clustered. Here, we show that the DNA cytosine deaminase APOBEC3B (A3B) is a likely source of these mutations. A3B mRNA is up-regulated in the majority of primary breast tumors and breast cancer cell lines. Tumors that express high levels of A3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous A3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell line extracts. Knockdown experiments show that endogenous A3B correlates with elevated levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced A3B over-expression causes cell cycle deviations, cell death, DNA fragmentation, γ-H2AX accumulation, and C-to-T mutations. Our data suggest a model in which A3B-catalyzed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumors evolve rapidly and manifest heterogeneity.