title: Functional conservation in human and Drosophila of Metazoan ADAR2 involved in RNA editing: loss of ADAR1 in insects.
abstract: Flies with mutations in the single Drosophila Adar gene encoding an RNA editing enzyme involved in editing 4% of all transcripts have severe locomotion defects and develop age-dependent neurodegeneration. Vertebrates have two ADAR-editing enzymes that are catalytically active; ADAR1 and ADAR2. We show that human ADAR2 rescues Drosophila Adar mutant phenotypes. Neither the short nuclear ADAR1p110 isoform nor the longer interferon-inducible cytoplasmic ADAR1p150 isoform rescue walking defects efficiently, nor do they correctly edit specific sites in Drosophila transcripts. Surprisingly, human ADAR1p110 does suppress age-dependent neurodegeneration in Drosophila Adar mutants whereas ADAR1p150 does not. The single Drosophila Adar gene was previously assumed to represent an evolutionary ancestor of the multiple vertebrate ADARs. The strong functional similarity of human ADAR2 and Drosophila Adar suggests rather that these are true orthologs. By a combination of direct cloning and searching new invertebrate genome sequences we show that distinct ADAR1 and ADAR2 genes were present very early in the Metazoan lineage, both occurring before the split between the Bilateria and Cnidarians. The ADAR1 gene has been lost several times, including during the evolution of insects and crustacea. These data complement our rescue results, supporting the idea that ADAR1 and ADAR2 have evolved highly conserved, distinct functions.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Liam P
authors.initials: LP
authors.lastname: Keegan
authors.forename: Leeane
authors.initials: L
authors.lastname: McGurk
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Palavicini
authors.forename: James
authors.initials: J
authors.lastname: Brindle
authors.forename: Simona
authors.initials: S
authors.lastname: Paro
authors.forename: Xianghua
authors.initials: X
authors.lastname: Li
authors.forename: Joshua J C
authors.initials: JJ
authors.lastname: Rosenthal
authors.forename: Mary A
authors.initials: MA
authors.lastname: O'Connell
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D017344:Genes, Insect; D006801:Humans; D008124:Locomotion; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology; D010802:Phylogeny; D017393:RNA Editing; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; C567956:Adar protein, Drosophila; D000243:Adenosine Deaminase