title: Viable RNaseH1 knockout mice show RNaseH1 is essential for R loop processing, mitochondrial and liver function.
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.
authors.affiliation: Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Walt F
authors.initials: WF
authors.lastname: Lima
authors.affiliation: Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Murray
authors.affiliation: Department of Functional Genomics, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Sagar S
authors.initials: SS
authors.lastname: Damle
authors.affiliation: Department of Functional Genomics, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Hart
authors.affiliation: Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.affiliation: Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Cheryl Li
authors.initials: CL
authors.lastname: De Hoyos
authors.affiliation: Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Xue-Hai
authors.initials: XH
authors.lastname: Liang
authors.affiliation: Department of Core Antisense Research, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA scrooke@ionisph.com.
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Crooke
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D004261:DNA Replication; D004272:DNA, Mitochondrial; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000235:genetics* / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D009928:Organ Specificity / Q000235:genetics; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016914:Ribonuclease H / Q000172:deficiency* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004272:DNA, Mitochondrial; D012313:RNA; D016914:Ribonuclease H; C078856:ribonuclease HI