The Wistar Institute, Philadelphia, PA, USA.
Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.
Nat Commun. 2021 Mar 12;12(1):1654. 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.
ADAR1 参与腺苷到次黄嘌呤 RNA 编辑。细胞质 ADAR1p150 编辑 3'UTR 双链 RNA，从而抑制干扰素的诱导。Adar1 基因敲除小鼠的胚胎致死、严重自身免疫性疾病 Aicardi-Goutières 综合征的发病机制以及癌症对免疫检查点阻断的耐药性都源于这种 ADAR1p150 功能的丧失。相比之下，核定位的 ADAR1p110 的生物学功能在很大程度上仍然未知。在这里，我们报告 ADAR1p110 在携带非典型端粒重复的癌细胞中调节 R 环形成和端粒处的基因组稳定性。ADAR1p110 编辑在经典和非经典变体重复之间形成的 RNA:DNA 杂交体中的 A-C 错配。将 A-C 错配编辑为 I:C 匹配对有助于 RNase H2 解决端粒 R 环。这种 ADAR1p110 依赖的端粒 R 环的控制对于端粒酶激活的癌细胞的持续增殖是必需的，揭示了 ADAR1p110 的致癌性质，并确定 ADAR1 为端粒酶阳性癌症有希望的治疗靶点。
