The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1

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.

Blockade of the lncRNA-DOT1L-LAMP5 axis enhances autophagy and promotes degradation of MLL fusion proteins

“…Several lncRNAs with unique expression patterns have been reported to play essential roles in various cellular and molecular mechanisms driving carcinogenesis [ 11 , 13 , 34 , 49 ]. For example, HOTAIR is frequently overexpressed in breast cancer and has been shown to promote cell growth and migration by modulating multiple signaling pathways, including FGFR and Wnt/catenin pathways; while can also facilitate the invasiveness and metastasis of breast cancer by stimulating gene expression via the targeting of PRC2 and reducing Akt/JNK signaling pathway [ 18 , 19 ].…”

“…We performed pull-down assays as previously described [ 24 , 34 ]. Pierce™ Magnetic RNA-Protein Pull-Down Kit (Thermo Fisher, USA) was used to perform the pull-down assays with the biotinylated LAMP5-AS1 and LAMP5-AS1 antisense.…”

Beyond ribosome biogenesis: noncoding nucleolar RNAs in physiology and tumor biology

“…Thus, the snoRNA parts might act as nucleolar or Cajal body targeting sequences, similar to what has been described and mechanistically uncovered for canonical snoRNAs [ 42 , 43 ]. Nucleolar localization has been demonstrated by RNA imaging and RT-qPCR analyses of cytoplasmic, nuclear and nucleolar RNA fractions also for LNC-SNO49AB in human leukemia cell lines [ 44 ].…”

“…Consistent with this, knockdown of LNC-SNO49AB potently suppresses leukemia progression in vitro and in vivo , as demonstrated in preclinical models. Collectively, these observations connect RNA editing with leukemogenesis and the biology of the nucleolus [ 44 ].…”

Small but strong: the emerging role of small nucleolar RNA in cardiovascular diseases

“…snoRNAs can be categorized into two main structural classes based on their structure, conserved sequence, and rRNA modification functions ( Huang W et al, 2022 ), C/D Box snoRNA ( Massenet et al, 2017 ; Yu et al, 2018 ; Baldini et al, 2021 ) and H/ACA Box snoRNA ( Stepanov et al, 2015 ; Caton et al, 2018 ; Trucks et al, 2021 ). C/D Box snoRNA and H/ACA Box snoRNA families predominate and have been exhaustively researched, whereas limited literature exist on small Cajal body (CB)-specific RNAs (scaRNAs) ( Deryusheva and Gall, 2013 ; Beneventi et al, 2021 ) and orphan snoRNAs ( Kocher et al, 2021 ; Xu et al, 2021 ).…”