Key result
IRES sequences in SINEUP RNAs enhance target mRNA translation by acting as effector domains.
Demonstrates that Internal Ribosome Entry Sites can act as Effector Domains in both linear and circular SINEUP RNAs to enhance translation.
Should not yet inform clinical practice; extends effector options for SINEUP RNAs in preclinical models.
SINEUPs are antisense long non-coding RNAs that enhance translation of overlapping sense mRNAs through the activity of two domains: a SINEB2 sequence UP-regulating translation (Effector Domain, ED) and an antisense region providing target specificity (Binding Domain, BD). In this study, we demonstrate that the invSINEB2 sequence from the natural SINEUP AS Uchl1 RNA is an Internal Ribosomal Entry Site (IRES) when acting in cis and that known viral and cellular IRES sequences can act as Effector Domain in synthetic SINEUPs. To identify natural IRES-containing, non-coding RNAs with SINEUP-like activity, we focused on circular RNAs showing that the non-coding hsa_circ_0085533 (circMyc), transcribed from the c-myc locus, enhances endogenous protein expression of its target PX Domain Containing Serine/Threonine Kinase Like (Pxk) by increasing mRNA association to polysomes. In summary, this study shows that natural and synthetic SINEUPs include linear and circular transcripts with an embedded IRES sequence as ED.
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D’Agostino et al. (2023) studied this question. SINEUPs and circRNAs with IRES sequences vs. Empty vectors or control constructs was evaluated on Protein translation enhancement. Internal Ribosomal Entry Sites (IRES) can act as Effector Domains in linear and circular SINEUP RNAs to enhance target mRNA translation, with natural circRNAs like circMyc increasing target protein levels.
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