Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinogenesis
  • Cell Line
  • Deoxyribonuclease (Pyrimidine Dimer) / genetics*
  • Deoxyribonuclease (Pyrimidine Dimer) / metabolism
  • Gene Expression
  • Humans
  • Inosine / metabolism
  • Liver / metabolism
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / genetics*
  • Liver Neoplasms, Experimental / metabolism
  • Liver Neoplasms, Experimental / pathology
  • Mice, Knockout
  • RNA Editing
  • RNA, Transfer / metabolism
  • Sequence Analysis, RNA
  • Sorafenib / pharmacology


  • Antineoplastic Agents
  • Inosine
  • RNA, Transfer
  • Sorafenib
  • Deoxyribonuclease (Pyrimidine Dimer)
  • Adenosine