Beyond the Transcript: Translating Non-Coding RNAs and Their Impact on Cellular Regulation

Non-coding RNAs (ncRNAs) constitute the majority of the human transcriptome and play diverse structural, catalytic, and regulatory roles. The ability of ncRNAs to be translated into functional peptides and microproteins expands our understanding of their regulatory potential beyond their established non-coding functions. Our comprehensive search identified 86 translating "non-coding" RNAs. While translating ncRNAs have traditionally been categorized as "peptide-encoding", in this study, we introduce a novel classification based on amino acid length, distinguishing their products as ncRNA encoded peptides (ncRNA-PEPs), which are less than 60 amino acids, or ncRNA encoded microproteins (ncRNA-MPs) ranging from 61 to 200 amino acids. These peptides and microproteins act as co-regulators in cell signaling, transcriptional regulation, and protein complex assembly, playing a role in both health and disease. We outline the molecular pathways by which ncRNA-PEPs and ncRNA-MPs could govern cell cycle progression, highlighting their influence on cell cycle transitions, oncogenic and tumor suppressor pathways, metabolic homeostasis, autophagy, and on key cell cycle regulators like PCNA, Rad18, and CDK-cyclin complexes. Furthermore, we highlight recent advancements in their detection and characterization, exploring their evolutionary origins, species-specific conservation, and potential therapeutic applications. Our findings underscore the emerging significance of ncRNA-PEPs and ncRNA-MPs as integral regulators of cellular processes, highlighting their functional versatility and opening promising avenues for further research and potential therapeutic applications.