TY - JOUR
T1 - ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells
AU - Shiromoto, Yusuke
AU - Sakurai, Masayuki
AU - Minakuchi, Moeko
AU - Ariyoshi, Kentaro
AU - Nishikura, Kazuko
N1 - Funding Information:
We thank Marcin Nowotny for RNase H2A, H2B, and H2C template plasmids, and Roger A. Greenberg and John M. Murray for a critical reading of the manuscript. We also thank the Protein Expression and Genomics Shared Facilities of The Wistar Institute Cancer Center, which are supported by the National Cancer Institute (P30 CA010815), for the services provided. The work was supported by grants from the National Institutes of Health (GM040536, CA175058, and GM130716), the Ellison Medical Foundation (AG-55-2281-09), the Macula Vision Research Foundation, and Emerson Collective to K.N. Y.S., and M.M. were supported in part by a fellowship from the Japan Society for the Promotion of Science (JSPS 2017-19) and the Uehara Memorial Foundation, respectively.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85102340079&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-21921-x
DO - 10.1038/s41467-021-21921-x
M3 - Article
C2 - 33712600
AN - SCOPUS:85102340079
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1654
ER -