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Long non-coding RNAs (lncRNAs) play crucial roles in regulating gene expression. Some are essential for organismal development and physiology, and they can contribute to diseases including cancer. Whilst most lncRNAs exhibit little sequence similarity, conservation of lncRNA transcription relative to neighbouring protein-coding genes suggests potential functional significance. Most positionally equivalent lncRNAs are uncharacterized and it remains unclear whether they exert similar roles in distant species. Here, we identified melanoma-associated lncRNAs predicted to be components of the MITF gene regulatory network in human melanoma that have positionally equivalent transcripts in zebrafish. We prioritized the cancer-associated lncRNA Differentiation Antagonizing Non-Protein Coding RNA (DANCR) as an exemplar for functional investigation. DANCR is a multi-exonic, cytoplasmically-enriched lncRNA and small RNA host gene transcribed from syntenic regions in the human and zebrafish genomes. MITF and c-MYC, key melanoma transcription factors, regulate human DANCR expression and melanoma patients with high DANCR display significantly decreased survival. DANCR is a melanoma oncogene that controls cancer-associated gene expression networks to promote human melanoma cell proliferation and migration. Zebrafish dancr is essential for embryonic development. It is dynamically expressed across multiple different cell types in the developing embryo, transcriptionally activated by mitfa during early zebrafish development and it regulates genes involved in cell death. Our work suggests that cancer-critical lncRNAs such as DANCR, expressed from similar regions in vertebrate genomes, may control related genes and processes involved in both embryonic development and tumorigenesis across species.

Squamous cell carcinoma cells experience high levels of replication stress due to oncogene-induced cell cycle deregulation. How such cells sustain rapid proliferation despite replication stress is still not fully understood. Here, we discovered, using rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analysis, that the squamous cell carcinoma oncoprotein YAP engages with RIF1, a key regulator of DNA replication and DNA damage repair under replication stress. RIF1 is highly expressed in human squamous cell carcinoma cell lines and tissues and upregulated during tumour progression. Depletion of RIF1 in squamous cell carcinoma cells exacerbates their endogenous replication stress. Mechanistically, we show that YAP interacts with RIF1 specifically at broken replication forks, and that YAP depletion impairs DNA damage repair under replication stress. Our results thus demonstrate that YAP’s oncogenic functions in squamous cancers involve both transcriptional and non-transcriptional mechanisms, the latter through interaction with RIF1 to dampen replication stress.