The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1.
The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1.
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snoRNA样lncRNA LNC-SNO49AB通过激活RNA编辑酶ADAR1驱动白血病
DOI：
10.1038/s41421-022-00460-9
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发表时间：
2022-11-01
期刊：
影响因子：
33.5
通讯作者：
Chen, Yue-Qin
中科院分区：
文献类型：
--
作者：
Huang, Wei;Sun, Yu-Meng;Pan, Qi;Fang, Ke;Chen, Xiao-Tong;Zeng, Zhan-Cheng;Chen, Tian-Qi;Zhu, Shun-Xin;Huang, Li-Bin;Luo, Xue-Qun;Wang, Wen-Tao;Chen, Yue-Qin
长非编码 RNA (lncRNA) 通常具有 5' 加帽和 3' 聚腺苷酸化，类似于大多数典型的 mRNA。然而，最近的研究揭示了一种与 snoRNA 相关的 lncRNA，具有独特的结构，引发了人们对它们如何加工以及如何发挥作用的疑问。在这里，我们鉴定了一种新的 snoRNA 相关 lncRNA，名为 LNC-SNO49AB，包含两个 C/D 盒 snoRNA 序列 SNORD49A 和 SNORD49B；并表明 LNC-SNO49AB 代表一种未报道的 lncRNA 类型，具有 5' 端 m7G 和 3' 端 snoRNA 结构。研究发现 LNC-SNO49AB 在白血病患者样本中高表达，沉默 LNC-SNO49AB 可在体外和体内显着抑制白血病进展。亚细胞定位表明LNC-SNO49AB主要位于核仁并与核仁蛋白fibrillarin相互作用。然而，我们发现LNC-SNO49AB在2′-O-甲基化调节（snoRNA的经典功能）中不起作用；相反，其snoRNA结构影响了lncRNA的稳定性。我们进一步证明LNC-SNO49AB可以直接与作用于RNA 1（ADAR1）的腺苷脱氨酶结合并促进其同源二聚化，从而具有高RNA A-to-I编辑活性。转录组分析表明，LNC-SNO49AB 和 ADAR1 敲低分别在下游信号通路（尤其是细胞周期通路）中具有非常相似的 RNA 修饰变化模式。这些发现表明一类以前未知的 snoRNA 相关 lncRNA，其通过核仁中独立于 snoRNA 引导的 rRNA 修饰的方式发挥作用。这是第一份关于 lncRNA 通过增强 ADAR1 二聚化来调节全基因组 RNA A-to-I 编辑以促进造血系统恶性肿瘤的报告，表明 LNC-SNO49AB 可能是针对白血病治疗的新靶点。
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.
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影响因子：
14.9
作者：
Incarnato D;Anselmi F;Morandi E;Neri F;Maldotti M;Rapelli S;Parlato C;Basile G;Oliviero S
通讯作者：
Oliviero S
影响因子：
16.8
作者：
Dhir, Ashish;Dhir, Somdutta;Proudfoot, Nick J.;Jopling, Catherine L.
通讯作者：
Jopling, Catherine L.
DOI：
10.1073/pnas.2017562118
发表时间：
2021-03-30
影响因子：
11.1
作者：
He, Daniel;Wu, David;Lim, Daniel A.
通讯作者：
Lim, Daniel A.
影响因子：
14.9
作者：
Eisenberg E;Adamsky K;Cohen L;Amariglio N;Hirshberg A;Rechavi G;Levanon EY
通讯作者：
Levanon EY
影响因子：
14.9
作者：
Dong ZW;Shao P;Diao LT;Zhou H;Yu CH;Qu LH
通讯作者：
Qu LH