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