title: The dsRBP and inactive editor ADR-1 utilizes dsRNA binding to regulate A-to-I RNA editing across the C. elegans transcriptome.
abstract: Inadequate adenosine-to-inosine editing of noncoding regions occurs in disease but is often uncorrelated with ADAR levels, underscoring the need to study deaminase-independent control of editing. C. elegans have two ADAR proteins, ADR-2 and the theoretically catalytically inactive ADR-1. Using high-throughput RNA sequencing of wild-type and adr mutant worms, we expand the repertoire of C. elegans edited transcripts over 5-fold and confirm that ADR-2 is the only active deaminase in vivo. Despite lacking deaminase function, ADR-1 affects editing of over 60 adenosines within the 3' UTRs of 16 different mRNAs. Furthermore, ADR-1 interacts directly with ADR-2 substrates, even in the absence of ADR-2, and mutations within its double-stranded RNA (dsRNA) binding domains abolish both binding and editing regulation. We conclude that ADR-1 acts as a major regulator of editing by binding ADR-2 substrates in vivo. These results raise the possibility that other dsRNA binding proteins, including the inactive human ADARs, regulate RNA editing through deaminase-independent mechanisms.
authors: Department of Biology, Indiana University, Bloomington, IN 47405, USA.
authors: Michael C
authors: MC
authors: Washburn
authors: Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093-0419, USA; Department of Cellular and Molecular Medicine, UCSD Stem Cell Program and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors: Boyko
authors: B
authors: Kakaradov
authors: Department of Cellular and Molecular Medicine, UCSD Stem Cell Program and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors: Balaji
authors: B
authors: Sundararaman
authors: Medical Sciences Program, Indiana University, Bloomington, IN 47405, USA.
authors: Emily
authors: E
authors: Wheeler
authors: Molecular Engineering Laboratory, A(∗)STAR, Singapore 138673, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 639798, Singapore.
authors: Shawn
authors: S
authors: Hoon
authors: Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093-0419, USA; Department of Cellular and Molecular Medicine, UCSD Stem Cell Program and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA; Molecular Engineering Laboratory, A(∗)STAR, Singapore 138673, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore. Electronic address: geneyeo@ucsd.edu.
authors: Gene W
authors: GW
authors: Yeo
authors: Medical Sciences Program, Indiana University, Bloomington, IN 47405, USA. Electronic address: hahundle@indiana.edu.
authors: Heather A
authors: HA
authors: Hundley
mesh_terms: D020413:3' Untranslated Regions; D000241:Adenosine / Q000235:genetics / Q000378:metabolism; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D007288:Inosine / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D017393:RNA Editing; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D020413:3' Untranslated Regions; D029742:Caenorhabditis elegans Proteins; D012330:RNA, Double-Stranded; D007288:Inosine; D000243:Adenosine Deaminase; C469735:Adr-1 protein, C elegans; C469736:Adr-2 protein, C elegans; D000241:Adenosine