ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells

• Published in: Nature communications 2021-03, Vol.12 (1), p.1654-1654, Article 1654
• Main Authors: Shiromoto, Yusuke, Sakurai, Masayuki, Minakuchi, Moeko, Ariyoshi, Kentaro, Nishikura, Kazuko
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/89; 14/19; 14/32; 14/63; 3' Untranslated regions; 38/22; 38/23; 38/32; 38/77; 38/88; 38/90; 42/70; 631/337/1645/1944; 631/67/69; 82/51; Adenosine; Adenosine Deaminase - genetics; Adenosine Deaminase - metabolism; Animals; Autoimmune diseases; Cancer; Cell Line, Tumor; Cell proliferation; Deoxyribonucleic acid; DNA; DNA Damage; Editing; Embryos; Genomes; Genomic Instability; Genomics; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Hybrids; Immune checkpoint; Interferon; Lethality; Mice; multidisciplinary; Neoplasms - genetics; Neoplasms - metabolism; Pathogenesis; R-Loop Structures; R-loops; Ribonuclease H2; Ribonucleic acid; RNA; RNA Editing; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Stability; Telomerase; Telomere - metabolism; Telomeres; Therapeutic targets; Transcriptome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21921-x

ADAR1 is involved in adenosine-to-inosine RNA editing. The cytoplasmic ADAR1p150 edits 3’UTR double-stranded RNAs and thereby suppresses induction of interferons. Loss of this ADAR1p150 function underlies the embryonic lethality of Adar1 null mice, pathogenesis of the severe autoimmune disease Aicardi-Goutières syndrome, and the resistance developed in cancers to immune checkpoint blockade. In contrast, the biological functions of the nuclear-localized ADAR1p110 remain largely unknown. Here, we report that ADAR1p110 regulates R-loop formation and genome stability at telomeres in cancer cells carrying non-canonical variants of telomeric repeats. ADAR1p110 edits the A-C mismatches within RNA:DNA hybrids formed between canonical and non-canonical variant repeats. Editing of A-C mismatches to I:C matched pairs facilitates resolution of telomeric R-loops by RNase H2. This ADAR1p110-dependent control of telomeric R-loops is required for continued proliferation of telomerase-reactivated cancer cells, revealing the pro-oncogenic nature of ADAR1p110 and identifying ADAR1 as a promising therapeutic target of telomerase positive cancers. One type of RNA editing involves ADAR-mediated conversion of adenosine to inosine. Here the authors show that ADAR1 nuclear isoform p110 regulates R loop formation and genome stability at telomeres in cancer cells.