TY - JOUR
T1 - Internal ribosome entry sites enhance translation in trans in antisense non-coding SINEUP and circular RNAs
AU - D'Agostino, Sabrina
AU - Tettey-Matey, Abraham
AU - Volpe, Massimiliano
AU - Pierattini, Bianca
AU - D'Agostino, Mattia
AU - Smělá, Denisa
AU - Ansaloni, Federico
AU - Broglia, Laura
AU - Lau, Pierre
AU - Peruzzo, Omar
AU - Braccia, Clarissa
AU - Armirotti, Andrea
AU - Scarpato, Margherita
AU - Damiani, Devid
AU - Ros, Gloria
AU - Di Carlo, Valerio
AU - Maniscalco, Federica
AU - Bechara, Elias
AU - Tartaglia, Gian Gaetano
AU - Carninci, Piero
AU - Santoro, Claudio
AU - Persichetti, Francesca
AU - Pandolfini, Luca
AU - Simonetti, Angelita
AU - Espinoza, Stefano
AU - Zucchelli, Silvia
AU - Sanges, Remo
AU - Bon, Carlotta
AU - Gustincich, Stefano
N1 - Publisher Copyright:
© 2025 The Author(s). Published by Oxford University Press.
PY - 2025/8/28
Y1 - 2025/8/28
N2 - Sequences in the 5′-untranslated regions of cellular and viral mRNAs can function as internal ribosome entry sites (IRESs), driving cis-acting translation of the downstream protein-coding open reading frame. Here we demonstrate that RNA sequences with either newly identified or well-characterized IRES activity can also induce trans-acting translation of an independent mRNA species through an antisense sequence. SINEUPs are antisense long non-coding RNAs that enhance the translation of overlapping sense mRNAs in trans by employing two critical domains: the invSINEB2 sequence, which up-regulates translation (effector domain), and an antisense region providing target specificity (binding domain). First, we show that the invSINEB2 from the natural SINEUP AS Uchl1 RNA acts as an IRES when functioning in cis. Next, we establish that known viral and cellular sequences with IRES activity can operate in trans as an effector domain in synthetic SINEUPs. To identify natural IRES-containing non-coding RNAs with transactivity, we found that the non-coding hsa_circ_0 085 533 (circMyc), transcribed from the c-myc locus, enhances protein expression of PX Domain Containing Serine/Threonine Kinase Like (PXK) by promoting mRNA association with polysomes through antisense sequences. These results suggest that SINEUPs and some circular RNAs are trans-acting IRESs, expanding the repertoire of molecular mechanisms to regulate translation.
AB - Sequences in the 5′-untranslated regions of cellular and viral mRNAs can function as internal ribosome entry sites (IRESs), driving cis-acting translation of the downstream protein-coding open reading frame. Here we demonstrate that RNA sequences with either newly identified or well-characterized IRES activity can also induce trans-acting translation of an independent mRNA species through an antisense sequence. SINEUPs are antisense long non-coding RNAs that enhance the translation of overlapping sense mRNAs in trans by employing two critical domains: the invSINEB2 sequence, which up-regulates translation (effector domain), and an antisense region providing target specificity (binding domain). First, we show that the invSINEB2 from the natural SINEUP AS Uchl1 RNA acts as an IRES when functioning in cis. Next, we establish that known viral and cellular sequences with IRES activity can operate in trans as an effector domain in synthetic SINEUPs. To identify natural IRES-containing non-coding RNAs with transactivity, we found that the non-coding hsa_circ_0 085 533 (circMyc), transcribed from the c-myc locus, enhances protein expression of PX Domain Containing Serine/Threonine Kinase Like (PXK) by promoting mRNA association with polysomes through antisense sequences. These results suggest that SINEUPs and some circular RNAs are trans-acting IRESs, expanding the repertoire of molecular mechanisms to regulate translation.
UR - https://www.scopus.com/pages/publications/105013605927
U2 - 10.1093/nar/gkaf788
DO - 10.1093/nar/gkaf788
M3 - Article
SN - 0305-1048
VL - 53
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 15
M1 - gkaf788
ER -