National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Dev Cell. 2021 Mar 8;56(5):702-715.e8. doi: 10.1016/j.devcel.2021.01.015. Epub 2021 Feb 19.
N6-methyladenosine (mA), one of the most prevalent RNA post-transcriptional modifications, is involved in numerous biological processes. In previous studies, the functions of mA were typically identified by perturbing the activity of the methyltransferase complex. Here, we dissect the contribution of mA to an individual-long noncoding RNA-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). The mutant MALAT1 lacking mA-motifs significantly suppressed the metastatic potential of cancer cells both in vitro and in vivo in mouse. Super-resolution imaging showed that the concatenated mA residues on MALAT1 acted as a scaffold for recruiting YTH-domain-containing protein 1 (YTHDC1) to nuclear speckles. We further reveal that the recognition of MALAT1-mA by YTHDC1 played a critical role in maintaining the composition and genomic binding sites of nuclear speckles, which regulate the expression of several key oncogenes. Furthermore, artificially tethering YTHDC1 onto mA-deficient MALAT1 largely rescues the metastatic potential of cancer cells.
N6-甲基腺苷（m6A）是最普遍的 RNA 转录后修饰之一，参与众多生物学过程。在以往的研究中，m6A 的功能通常是通过干扰甲基转移酶复合物的活性来确定的。在这里，我们剖析了 m6A 对单个长非编码 RNA-转移相关肺腺癌转录本 1（MALAT1）的贡献。缺乏 m6A 基序的突变 MALAT1 显著抑制了体外和体内小鼠中癌细胞的转移潜力。超分辨率成像显示，MALAT1 上串联的 m6A 残基作为一种支架，募集 YTH 结构域包含蛋白 1（YTHDC1）到核斑。我们进一步揭示，YTHDC1 对 MALAT1-m6A 的识别在维持核斑的组成和基因组结合位点方面起着关键作用，从而调节几个关键癌基因的表达。此外，人工将 YTHDC1 固定在缺乏 m6A 的 MALAT1 上，在很大程度上挽救了癌细胞的转移潜力。
