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Nucleic Acids Res. 2020 Feb 21. pii: gkaa115. doi: 10.1093/nar/gkaa115. [Epub ahead of print]

Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma.

Author information

1
Research Institute of Internal Medicine, Oslo University Hospital HF, Rikshospitalet, NO-0424 Oslo, Norway.
2
Department of Microbiology, Oslo University Hospital HF, Rikshospitalet and University of Oslo, NO-0424 Oslo, Norway.
3
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway.
4
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, NO-0317 Oslo, Norway.
5
Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, NO-0424 Oslo, Norway.
6
Department of Molecular Medicine, Institute of Basic Medical Sciences, University ofOslo, NO-0317 Oslo, Norway.

Abstract

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.

PMID:
32083667
DOI:
10.1093/nar/gkaa115

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