Balaji Adarsh, Hall Simone, Johnson Raul, Zhu Jonathan, Ellis Lauren, McHugh Colleen A
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States.
Nucleic Acids Res. 2025 Aug 11;53(15). doi: 10.1093/nar/gkaf784.
Messenger RNAs (mRNAs) are subject to multiple layers of gene expression regulation, enabling the production of a large diversity of RNA transcripts and encoded proteins from a smaller number of genes in the human genome. We find that the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) non-coding RNA regulates mRNA processing through direct RNA-RNA and RNA-protein interactions. MALAT1 interacts with both the TAR DNA binding protein (TDP-43) and the spermine/spermidine acetyltransferase SAT1 pre-mRNA to enhance alternative splicing of SAT1 through direct, sequence-specific interactions. MALAT1 interaction with TDP-43 and SAT1 increases TDP-43 binding affinity for SAT1 pre-mRNA by coordinating tripartite RNA-RNA-protein interactions. These tripartite interactions enhance SAT1 alternative splicing. This mechanism of pre-mRNA processing may not be limited to MALAT1, TDP-43, and SAT1. Similarly, alternative splicing of the liprin-α3 PPFIA3 pre-mRNA at exon 16 by the cleavage stimulation factor subunit 2 protein is enhanced by sequence-specific interactions with MALAT1 RNA. We conclude that the abundant MALAT1 non-coding RNA contains modular RNA-RNA and RNA-protein binding regions that facilitate the processing of mRNA transcripts relevant for neuronal function.
信使核糖核酸（mRNA）受到多层基因表达调控，从而能够从人类基因组中数量较少的基因产生大量多样的RNA转录本和编码蛋白质。我们发现，转移相关的肺腺癌转录本1（MALAT1）非编码RNA通过直接的RNA-RNA和RNA-蛋白质相互作用来调节mRNA加工。MALAT1与TAR DNA结合蛋白（TDP-43）以及精胺/亚精胺乙酰转移酶SAT1前体mRNA相互作用，通过直接的序列特异性相互作用增强SAT1的可变剪接。MALAT1与TDP-43和SAT1的相互作用通过协调三方RNA-RNA-蛋白质相互作用，增加了TDP-43对SAT1前体mRNA的结合亲和力。这些三方相互作用增强了SAT1的可变剪接。这种前体mRNA加工机制可能不限于MALAT1、TDP-43和SAT1。同样，通过与MALAT1 RNA的序列特异性相互作用，切割刺激因子亚基2蛋白对liprin-α3（PPFIA3）前体mRNA外显子16的可变剪接得到增强。我们得出结论，丰富的MALAT1非编码RNA包含模块化的RNA-RNA和RNA-蛋白质结合区域，这些区域有助于处理与神经元功能相关的mRNA转录本。
