Secondary Structural Model of Human MALAT1 Reveals Multiple Structure–Function Relationships

Abstract

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.

Mechanisms of Long Non-Coding RNAs in Cancers and Their Dynamic Regulations

“…PAN lncRNA folds into three branched domains and its 5 Mta responsive element (MRE) region and 3 expression and nuclear retention element (ENE) are identified in a larger structural context. A recent study identified the secondary structure of MALAT1, an important cancer-related lncRNA, in vitro and in various human cell lines [92]. In addition to providing protein/RNA-binding structural information, this study reveals that the structure of lncRNA MALAT1 can be perturbed by RNA modifications, mutations in cancer, and single-nucleotide polymorphisms.…”

ATF2-Induced lncRNA GAS8-AS1 Promotes Autophagy of Thyroid Cancer Cells by Targeting the miR-187-3p/ATG5 and miR-1343-3p/ATG7 Axes

“…39 For example, a change in the secondary structure of MALAT1 disrupted miR-217-5p binding to MALAT1. 40 Pan et al. 10 demonstrated that the c.713A>G/714T>C dinucleotide substitution induces a significant change in the GAS8-AS1 secondary structure, so we speculated that the difference of the secondary structure between the mutant and WT GAS8-AS1 may have caused this result.…”

Editing and Chemical Modifications on Non-Coding RNAs in Cancer: A New Tale with Clinical Significance

“…Additionally, Brown et al demonstrated that the METTL16 binds at the 3′ UTR triple helical region of MALAT1 [ 113 ]. Moreover, m 6 A changes in MALAT1 alter its binding capacity of miRNAs involved in cancer [ 114 ]. RNA-binding motif protein 15 (RBM15) and RMB15B are also part of the METTL3 complex and target the X-inactive specific transcript ( XIST ) lncRNA [ 115 ].…”