Research Institute of Internal Medicine, Oslo University Hospital HF, Rikshospitalet, NO-0424 Oslo, Norway.
Department of Microbiology, Oslo University Hospital HF, Rikshospitalet and University of Oslo, NO-0424 Oslo, Norway.
Nucleic Acids Res. 2020 May 7;48(8):4463-4479. doi: 10.1093/nar/gkaa115.
Endonuclease V (EndoV) is a conserved inosine-specific ribonuclease with unknown biological function. Here, we present the first mouse model lacking EndoV, which is viable without visible abnormalities. We show that endogenous murine EndoV cleaves inosine-containing RNA in vitro, nevertheless a series of experiments fails to link an in vivo function to processing of such transcripts. As inosine levels and adenosine-to-inosine editing often are dysregulated in hepatocellular carcinoma (HCC), we chemically induced HCC in mice. All mice developed liver cancer, however, EndoV-/- tumors were significantly fewer and smaller than wild type tumors. Opposed to human HCC, adenosine deaminase mRNA expression and site-specific editing were unaltered in our model. Loss of EndoV did not affect editing levels in liver tumors, however mRNA expression of a selection of cancer related genes were reduced. Inosines are also found in certain tRNAs and tRNAs are cleaved during stress to produce signaling entities. tRNA fragmentation was dysregulated in EndoV-/- livers and apparently, inosine-independent. We speculate that the inosine-ribonuclease activity of EndoV is disabled in vivo, but RNA binding allowed to promote stabilization of transcripts or recruitment of proteins to fine-tune gene expression. The EndoV-/- tumor suppressive phenotype calls for related studies in human HCC.
内切核酸酶 V（EndoV）是一种保守的肌苷特异性核糖核酸酶，其生物学功能未知。在这里，我们展示了第一个缺乏 EndoV 的小鼠模型，该模型在没有明显异常的情况下是可行的。我们表明，内源性的鼠 EndoV 在体外切割含有肌苷的 RNA，但一系列实验未能将其体内功能与这些转录本的加工联系起来。由于肌苷水平和腺嘌呤到肌苷的编辑在肝细胞癌（HCC）中经常失调，我们用化学方法诱导小鼠发生 HCC。所有小鼠都发展为肝癌，但 EndoV-/- 肿瘤比野生型肿瘤明显更少和更小。与人类 HCC 相反，我们的模型中腺苷脱氨酶 mRNA 表达和特异性编辑没有改变。EndoV 的缺失并不影响肝癌中的编辑水平，但一些与癌症相关基因的 mRNA 表达减少。肌苷也存在于某些 tRNA 中，tRNA 在应激时被切割产生信号实体。EndoV-/- 肝脏中的 tRNA 片段化失调，显然与肌苷无关。我们推测，EndoV 的肌苷核糖核酸酶活性在体内失活，但 RNA 结合允许促进转录本的稳定或招募蛋白质来微调基因表达。EndoV-/- 的肿瘤抑制表型呼吁在人类 HCC 中进行相关研究。
