Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-21921-x
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Funding
- National Cancer Institute [P30 CA010815]
- National Institutes of Health [GM040536, CA175058, GM130716]
- Ellison Medical Foundation [AG-55-2281-09]
- Macula Vision Research Foundation
- Emerson Collective
- Japan Society for the Promotion of Science (JSPS)
- Uehara Memorial Foundation
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The study shows that the nuclear isoform p110 of ADAR1 regulates R loop formation and genome stability at telomeres in cancer cells. Editing of A-C mismatches by ADAR1p110 assists in resolving telomeric R loops, crucial for the proliferation of telomerase-positive cancer cells. These findings highlight the pro-oncogenic nature of ADAR1p110 and identify ADAR1 as a promising therapeutic target for telomerase positive cancers.
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-Goutieres 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.
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