Background: Long non-coding RNAs (lncRNAs) exhibit rapid evolutionary turnover, often driven by genomic duplication. How paralogous lncRNAs maintain, partition, or diverge in function across distinct genomic contexts remains poorly understood. The evolutionarily conserved lncRNA MORRBID and its primate-specific paralog CYTOR provide a natural framework to interrogate the functional consequences of lncRNA duplication. Results: Although CYTOR and MORRBID have acquired distinct transcript variants influenced by their divergent genomic environments, we demonstrate that they maintain a robust, shared core function encoded by near-identical dominant two-exon transcripts. Using SNP-based paralog-specific quantification, we found that CYTOR contributes more strongly to the shared transcript pool, while both transcripts localize predominantly to the cytoplasm, consistent with a shared trans-acting function. Simultaneous repression of CYTOR and MORRBID consistently impairs cell adhesion and migration across multiple cancer models. Mechanistically, the shared CYTOR/MORRBID transcript pool associates with MEK2 and sustains MEK-ERK signaling. This signaling axis promotes FOSL1 expression and AP-1-linked transcriptional output, including expression of the downstream effector EPHA4, whose role was supported by rescue experiments. Patient tumor transcriptomes and healthy single-cell datasets further supported the associated mesenchymal, adhesion, and epithelial-mesenchymal transition program. Conclusions: Our findings establish that paralogous lncRNAs can retain a conserved mechanistic core despite context-dependent transcriptional divergence. The CYTOR/MORRBID transcript pool defines a shared lncRNA signaling module that supports MAPK-ERK signaling and adhesion-migration programs across cancer and mesenchymal-like cellular contexts. This defines a unified mechanistic framework for the shared core function of these widely studied paralogous lncRNAs.
Ali-Nasser, T., Khoury, C., Altalef Mishaan, S., Bhonkar, O., Lin, Z., Qian, Y., Lahoud-Jeries, N. L.-J., Aran, D., Bester, A. C.
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