Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Chemistry and Biochemistry, Biomolecular Science and Engineering Program, University of California at Santa Barbara, Santa Barbara, CA 93106, USA.
Int J Mol Sci. 2019 Nov 9;20(22):5610. doi: 10.3390/ijms20225610.
Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an abundant nuclear-localized long noncoding RNA (lncRNA) that has significant roles in cancer. While the interacting partners and evolutionary sequence conservation of MALAT1 have been examined, much of the structure of MALAT1 is unknown. Here, we propose a hypothetical secondary structural model for 8425 nucleotides of human MALAT1 using three experimental datasets that probed RNA structures in vitro and in various human cell lines. Our model indicates that approximately half of human MALAT1 is structured, forming 194 helices, 13 pseudoknots, five structured tetraloops, nine structured internal loops, and 13 intramolecular long-range interactions that give rise to several multiway junctions. Evolutionary conservation and covariation analyses support 153 of 194 helices in 51 mammalian MALAT1 homologs and 42 of 194 helices in 53 vertebrate MALAT1 homologs, thereby identifying an evolutionarily conserved core that likely has important functional roles in mammals and vertebrates. Data mining revealed that RNA modifications, somatic cancer-associated mutations, and single-nucleotide polymorphisms may induce structural rearrangements that sequester or expose binding sites for several cancer-associated microRNAs. Our findings reveal new mechanistic leads into the roles of MALAT1 by identifying several intriguing structure-function relationships in which the dynamic structure of MALAT1 underlies its biological functions.
人类转移相关肺腺癌转录物 1（MALAT1）是一种丰富的核定位长非编码 RNA（lncRNA），在癌症中具有重要作用。虽然已经研究了 MALAT1 的相互作用伙伴和进化序列保守性，但 MALAT1 的大部分结构仍然未知。在这里，我们使用三个实验数据集，对体外和各种人类细胞系中的 RNA 结构进行了探测，提出了人类 MALAT1 的 8425 个核苷酸的假设二级结构模型。我们的模型表明，大约一半的人类 MALAT1 是结构化的，形成 194 个螺旋、13 个假结、5 个结构四链体、9 个结构内部环和 13 个分子内长程相互作用，形成几个多叉结。进化保守性和共变分析支持 51 种哺乳动物 MALAT1 同源物中的 194 个螺旋中的 153 个，以及 53 种脊椎动物 MALAT1 同源物中的 194 个螺旋中的 42 个，从而鉴定出一个可能在哺乳动物和脊椎动物中具有重要功能作用的进化保守核心。数据挖掘揭示了 RNA 修饰、体细胞癌症相关突变和单核苷酸多态性可能诱导结构重排，从而隔离或暴露几个癌症相关 microRNA 的结合位点。我们的研究结果通过鉴定 MALAT1 的几个有趣的结构-功能关系，为 MALAT1 的作用提供了新的机制线索，其中 MALAT1 的动态结构是其生物学功能的基础。
