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Nucleic Acids Res. 2016 Jun 20;44(11):5299-312. doi: 10.1093/nar/gkw350. Epub 2016 Apr 29.

Viable RNaseH1 knockout mice show RNaseH1 is essential for R loop processing, mitochondrial and liver function.

Author information

1
Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
2
Department of Functional Genomics, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
3
Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
4
Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA scrooke@ionisph.com.

Abstract

Viable constitutive and tamoxifen inducible liver-specific RNase H1 knockout mice that expressed no RNase H1 activity in hepatocytes showed increased R-loop levels and reduced mitochondrial encoded DNA and mRNA levels, suggesting impaired mitochondrial R-loop processing, transcription and mitochondrial DNA replication. These changes resulted in mitochondrial dysfunction with marked changes in mitochondrial fusion, fission, morphology and transcriptional changes reflective of mitochondrial damage and stress. Liver degeneration ensued, as indicated by apoptosis, fibrosis and increased transaminase levels. Antisense oligonucleotides (ASOs) designed to serve as substrates for RNase H1 were inactive in the hepatocytes from the RNase H1 knockout mice and in vivo, demonstrating that RNase H1 is necessary for the activity of DNA-like ASOs. During liver regeneration, a clone of hepatocytes that expressed RNase H1 developed and partially restored mitochondrial and liver function.

PMID:
27131367
PMCID:
PMC4914116
DOI:
10.1093/nar/gkw350
[Indexed for MEDLINE]
Free PMC Article

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