DIS3 ribonuclease prevents the cytoplasmic accumulation of lncRNAs carrying non-canonical ORFs.

Abstract
Some of the long noncoding (lnc)RNAs harbor potential to produce functional micro peptides. Despite their increasing significance, the regulatory dynamics of cytoplasmic lncRNA expression, decay, and translation remain poorly understood. Here, we investigate the role of ribonucleases in controlling cytoplasmic levels of lncRNAs. We observed large accumulation of a previously assumed nuclear-localized DIS3-sensitive transcripts (DISTs), contrary to low number of lncRNAs sensitive to the cytoplasmic XRN1. Approximately 14.5% of DIS3-sensitive transcripts (DISTs) contain actively translated open reading frames (ORFs), including some with typical protein-coding genes features: polyA enrichment and conservation across primates. Importantly, transcriptomic analysis of patients cases with DIS3 mutations in the multiple myeloma, a bone marrow cancer, showed shared subgroup of overexpressed translatable DISTs. Our immunopeptidomic proves the association of DISTs-derived peptides with the major histocompatibility class I complex. Furthermore, the low expression of DISTs in healthy tissues highlights the potential of DIST-ORFs as sources of tumor-specific antigens.