Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma
Kong, Xiang Yi; Vik, Erik Sebastian; Nawaz, Meh Sameen; Berges, Natalia; Dahl, Tuva Børresdatter; Vågbø, Cathrine; Suganthan, Rajikala; Segers, Filip; Holm, Sverre; Quiles-Jimenez, Ana; Gregersen, Ida; Fladeby, Cathrine; Aukrust, Pål; Bjørås, Magnar; Klungland, Arne; Halvorsen, Bente; Alseth, Ingrun
Journal article, Peer reviewed
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Original versionKong XY, Vik SV, Nawaz MS, Berges N, Dahl TB, Vågbø CB, Suganthan R, Segers F, Holm S, Quiles-Jimenez, Gregersen I, Fladeby C, Aukrust P, Bjørås M, Klungland A, Halvorsen BE, Alseth I. Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma. Nucleic Acids Research. 2020 https://doi.org/10.1093/nar/gkaa115
Endonuclease V (EndoV) is a conserved inosinespecific 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 finetune gene expression. The EndoV−/− tumor suppressive phenotype calls for related studies in human HCC.