癌症是由于基因组突变而引发的，其随后的进展部分依赖于核糖体产量的增加，以维持高水平的蛋白质合成以促进不受控制的细胞生长。最近，胞苷脱氨酶被发现是癌症诱变的来源。为了在这两种癌症驱动过程之间建立联系，我们研究了胞苷脱氨酶蛋白家族在人类核糖体生物合成中的潜在作用。我们通过我们实验室建立的用于发现 MCF10A 细胞核仁功能调节因子的筛选平台，鉴定并验证了 AP​​OBEC3A 和 APOBEC4 作为新型核糖体生物合成因子。通过 siRNA 耗竭实验，我们强调了 APOBEC3A 在制造核糖体中的要求以及在形成大亚基 5.8S 和 28S 核糖体 (r)RNA 的加工和成熟步骤中的特定作用。我们证明 APOBEC3A 的一个子集存在于核仁内并与关键的核糖体生物发生因子相关。通过野生型和催化死亡突变 APOBEC3A 的瞬时过度表达揭示了机制见解，这两者都增加了细胞生长和蛋白质合成。通过创新的核 RNA 测序方法，我们仅在 pre-rRNA 和 pre-mRNA 上识别出适度预测的 APOBEC3A C-to-U 靶位点。我们的工作揭示了 APOBEC3A 在核糖体生物发生中的潜在直接作用，可能与其编辑功能无关。更广泛地说，我们通过其在核糖体生物发生中的功能发现了 APOBEC3A 在癌症病理学中的额外功能，扩大了其作为癌症治疗靶点的相关性。版权所有：© 2024 McCool 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

Cancer initiates as a consequence of genomic mutations and its subsequent progression relies in part on increased production of ribosomes to maintain high levels of protein synthesis for unchecked cell growth. Recently, cytidine deaminases have been uncovered as sources of mutagenesis in cancer. In an attempt to form a connection between these 2 cancer driving processes, we interrogated the cytidine deaminase family of proteins for potential roles in human ribosome biogenesis. We identified and validated APOBEC3A and APOBEC4 as novel ribosome biogenesis factors through our laboratory's established screening platform for the discovery of regulators of nucleolar function in MCF10A cells. Through siRNA depletion experiments, we highlight APOBEC3A's requirement in making ribosomes and specific role within the processing and maturation steps that form the large subunit 5.8S and 28S ribosomal (r)RNAs. We demonstrate that a subset of APOBEC3A resides within the nucleolus and associates with critical ribosome biogenesis factors. Mechanistic insight was revealed by transient overexpression of both wild-type and a catalytically dead mutated APOBEC3A, which both increase cell growth and protein synthesis. Through an innovative nuclear RNA sequencing methodology, we identify only modest predicted APOBEC3A C-to-U target sites on the pre-rRNA and pre-mRNAs. Our work reveals a potential direct role for APOBEC3A in ribosome biogenesis likely independent of its editing function. More broadly, we found an additional function of APOBEC3A in cancer pathology through its function in ribosome biogenesis, expanding its relevance as a target for cancer therapeutics.Copyright: © 2024 McCool et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.