Two APOBEC DNA cytosine deaminase enzymes, APOBEC3A and APOBEC3B, generate somatic mutations in cancer, thereby driving tumour development and drug resistance. Here, we used single-cell RNA sequencing to study APOBEC3A and APOBEC3B expression in healthy and malignant mucosal epithelia, validating key observations with immunohistochemistry, spatial transcriptomics and functional experiments. Whereas APOBEC3B is expressed in keratinocytes entering mitosis, we show that APOBEC3A expression is confined largely to terminally differentiating cells and requires grainyhead-like transcription factor 3 (GRHL3). Thus, in normal tissue, neither deaminase appears to be expressed at high levels during DNA replication, the cell-cycle stage associated with APOBEC-mediated mutagenesis. In contrast, in squamous cell carcinoma we find that, there is expansion of GRHL3expression and activity to a subset of cells undergoing DNA replication and concomitant extension of APOBEC3A expression to proliferating cells. These findings suggest that APOBEC3A may play a functional role during keratinocyte differentiation, and offer a mechanism for acquisition of APOBEC3A mutagenic activity in tumours.

中文翻译：

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分化信号通过 GRHL3 诱导鳞状上皮细胞癌和鳞状细胞癌APOBEC3A表达。


两种 APOBEC DNA 胞嘧啶脱氨酶 APOBEC3A 和 APOBEC3B 在癌症中产生体细胞突变，从而驱动肿瘤发展和耐药性。在这里，我们使用单细胞 RNA 测序来研究健康和恶性粘膜上皮细胞中APOBEC3A和APOBEC3B表达，通过免疫组织化学、空间转录组学和功能实验验证关键观察结果。虽然 APOBEC3B 在进入有丝分裂的角质形成细胞中表达，但我们表明APOBEC3A表达主要局限于终末分化细胞，并且需要颗粒状头状转录因子 3 （GRHL3）。因此，在正常组织中，两种脱氨酶在 DNA 复制期间似乎都没有高水平表达，DNA 复制是与 APOBEC 介导的诱变相关的细胞周期阶段。相比之下，在鳞状细胞癌中，我们发现 GRHL3 表达和活性扩展到经历 DNA 复制的细胞亚群，并伴随着 APOBEC3A 表达扩展到增殖细胞。这些发现表明，APOBEC3A可能在角质形成细胞分化过程中发挥功能作用，并为在肿瘤中获得APOBEC3A诱变活性提供了一种机制。