Frank Filipp, Kavousi Nadieh, Bountali Aikaterini, Dammer Eric B, Mourtada-Maarabouni Mirna, Ortlund Eric A
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
Faculty of Natural Sciences, School of Life Sciences, Keele University, Keele ST5 5BG, UK.
Cell Rep. 2020 Jul 21;32(3):107933. doi: 10.1016/j.celrep.2020.107933.
There is increasing evidence that the architecture of long non-coding RNAs (lncRNAs)-just like that of proteins-is hierarchically organized into independently folding sub-modules with distinct functions. Studies characterizing the cellular activities of such modules, however, are rare. The lncRNA growth arrest specific 5 (GAS5) is a key regulator of cell survival in response to stress and nutrient availability. We use SHAPE-MaP to probe the structure of GAS5 and identify three separate structural modules that act independently in leukemic T cells. The 5' terminal module with low secondary structure content affects basal survival and slows the cell cycle, whereas the highly structured core module mediates the effects of mammalian target of rapamycin (mTOR) inhibition on cell growth. These results highlight the central role of GAS5 in regulating cell survival and reveal how a single lncRNA transcript utilizes a modular structure-function relationship to respond to a variety of cellular stresses under various cellular conditions.
越来越多的证据表明，长链非编码RNA（lncRNA）的结构——就像蛋白质的结构一样——是分层组织成具有不同功能的独立折叠子模块。然而，表征此类模块细胞活性的研究却很少见。lncRNA生长停滞特异性5（GAS5）是细胞对应激和营养可用性作出反应时细胞存活的关键调节因子。我们使用SHAPE-MaP来探测GAS5的结构，并确定了三个在白血病T细胞中独立起作用的单独结构模块。二级结构含量低的5'末端模块影响基础存活并减缓细胞周期，而高度结构化的核心模块介导雷帕霉素哺乳动物靶标（mTOR）抑制对细胞生长的影响。这些结果突出了GAS5在调节细胞存活中的核心作用，并揭示了单个lncRNA转录本如何利用模块化的结构-功能关系在各种细胞条件下应对多种细胞应激。
