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

Autor:	Lima WF; Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Murray HM; Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Damle SS; Department of Functional Genomics, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Hart CE; Department of Functional Genomics, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Hung G; Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., De Hoyos CL; Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Liang XH; Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Crooke ST; Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA scrooke@ionisph.com.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2016 Jun 20; Vol. 44 (11), pp. 5299-312. Date of Electronic Publication: 2016 Apr 29.
DOI:	10.1093/nar/gkw350
Abstrakt:	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. (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu