The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1
Wei Huang, Yumeng Sun, Qi Pan, Ke Fang, Xiaotong Chen, Zhan‐Cheng Zeng, Tian-Qi Chen, Shun-Xin Zhu, Libin Huang, Xue‐Qun Luo, Wentao Wang, Yujie Chen
Abstract
Long noncoding RNAs (lncRNAs) are usually 5' capped and 3' polyadenylated, similar to most typical mRNAs. However, recent studies revealed a type of snoRNA-related lncRNA with unique structures, leading to questions on how they are processed and how they work. Here, we identify a novel snoRNA-related lncRNA named LNC-SNO49AB containing two C/D box snoRNA sequences, SNORD49A and SNORD49B; and show that LNC-SNO49AB represents an unreported type of lncRNA with a 5'-end m7G and a 3'-end snoRNA structure. LNC-SNO49AB was found highly expressed in leukemia patient samples, and silencing LNC-SNO49AB dramatically suppressed leukemia progression in vitro and in vivo. Subcellular location indicated that the LNC-SNO49AB is mainly located in nucleolus and interacted with the nucleolar protein fibrillarin. However, we found that LNC-SNO49AB does not play a role in 2'-O-methylation regulation, a classical function of snoRNA; instead, its snoRNA structure affected the lncRNA stability. We further demonstrated that LNC-SNO49AB could directly bind to the adenosine deaminase acting on RNA 1(ADAR1) and promoted its homodimerization followed by a high RNA A-to-I editing activity. Transcriptome profiling shows that LNC-SNO49AB and ADAR1 knockdown respectively share very similar patterns of RNA modification change in downstream signaling pathways, especially in cell cycle pathways. These findings suggest a previously unknown class of snoRNA-related lncRNAs, which function via a manner in nucleolus independently on snoRNA-guide rRNA modification. This is the first report that a lncRNA regulates genome-wide RNA A-to-I editing by enhancing ADAR1 dimerization to facilitate hematopoietic malignancy, suggesting that LNC-SNO49AB may be a novel target in therapy directed to leukemia.