Chromatin-associated orphan snoRNA regulates DNA damage-mediated differentiation via a non-canonical complex
Chromatin-associated orphan snoRNA regulates DNA damage-mediated differentiation via a non-canonical complex
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染色质相关孤儿 snoRNA 通过非典型复合物调节 DNA 损伤介导的分化
DOI：
10.1016/j.celrep.2022.110421
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发表时间：
2022-03-29
期刊：
影响因子：
8.8
通讯作者：
Chen, Yue-Qin
中科院分区：
文献类型：
--
作者：
Han, Cai;Sun, Lin-Yu;Chen, Yue-Qin
核仁小RNA（snoRNA）是一类引导核糖体RNA修饰的同源非编码RNA。然而，被称为孤儿的snoRNA在很大程度上具有未知的功能。在这里，我们系统地分析了哺乳动物细胞中的染色质相关snoRNA（casnoRNA），并鉴定了一个响应DNA损伤应激的孤儿casnoRNA亚组，其中SNORA 73显示染色质富集最显著的减少。下调的SNORA 73在造血系统恶性肿瘤中维持癌症基因组稳定性和分化阻断。从机制上讲，SNORA 73的5'端非规范结构casnoRNA对其功能和与聚（ADP-核糖）聚合酶I（PARPl）的结合至关重要。SNORA 73通过与PARP 1和典型H/ACA蛋白DKC 1/NHP 2形成小核仁核糖核蛋白（snoRNP）来抑制PARP 1自身PAR化以影响癌症基因组稳定性。我们的研究结果揭示了孤儿snoRNA作为casnoRNA的作用，并强调了snoRNA的非规范结构与其功能多样性之间的联系。
Small nucleolar RNAs (snoRNAs) are commonly acknowledged as a class of homogeneous non-coding RNAs that guide ribosomal RNA modifications. However, snoRNAs referred to as orphans have largely unknown functions. Here, we systematically profile chromatin-associated snoRNAs (casnoRNAs) in mammalian cells and identify a subgroup of orphan casnoRNAs responding to DNA damage stress, among which SNORA73 shows the most marked reduction in chromatin enrichment. Downregulated SNORA73 maintains cancer genome stability and differentiation block in hematopoietic malignancy. Mechanistically, casnoRNA the 5' end non-canonical structure of SNORA73 is critical for its function and binding to poly (ADP-ribose) polymerase 1 (PARP1). SNORA73 inhibits PARP1 auto-PARylation to affect cancer genome stability by forming a small nucleolar ribonucleoprotein (snoRNP) with PARP1 and canonical H/ACA proteins DKC1/NHP2. Our findings reveal the role of an orphan snoRNA serving as casnoRNA and highlights a link between non-canonical structure of snoRNA and their functional diversity.