Abstract
The role of G-quadruplex (G4) RNA structures is multifaceted and controversial. Here, we have used as a model the EBV-encoded EBNA1 and the Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded LANA1 mRNAs. We have compared the G4s in these two messages in terms of nucleolin binding, nuclear mRNA retention, and mRNA translation inhibition and their effects on immune evasion. The G4s in the EBNA1 message are clustered in one repeat sequence and the G4 ligand PhenDH2 prevents all G4-associated activities. The RNA G4s in the LANA1 message take part in similar multiple mRNA functions but are spread throughout the message. The different G4 activities depend on flanking coding and non-coding sequences and, interestingly, can be separated individually. Together, the results illustrate the multifunctional, dynamic and context-dependent nature of G4 RNAs and highlight the possibility to develop ligands targeting specific RNA G4 functions. The data also suggest a common multifunctional repertoire of viral G4 RNA activities for immune evasion.
Highlights
RNA–protein interactions are key regulators of the selective processing of RNAs which includes RNA splicing, localisation, translation, and stability, and are involved in various cellular processes (Lewis et al, 2017; Duss et al, 2019; Rodgers & Woodson, 2019) including embryonic development (Beaudoin et al, 2018), neuronal activity (Lin et al, 2020), and oncogenesis (Ceci et al, 2021), to mention some
To confirm the binding of the G4 ligands we selected, namely, PhenDC3 and PhenDH2, on LANA1 RNA G4 structures, two quadruplex-prone G-rich short RNA sequences (LANA13 and LANA16 with QGRS scores of 21 and 18, respectively, Fig 1B) from the LANA1 Central Repeat (CR) domains, which have been already identified for their potential to form multiple quadruplex structures (Dabral et al, 2019), have been selected
These data support the formation of G4 structures within the LANA1 CR domains and the possibility of targeting them with high affinity ligands such as PhenDC3 and PhenDH2
Summary
RNA–protein interactions are key regulators of the selective processing of RNAs which includes RNA splicing, localisation, translation, and stability, and are involved in various cellular processes (Lewis et al, 2017; Duss et al, 2019; Rodgers & Woodson, 2019) including embryonic development (Beaudoin et al, 2018), neuronal activity (Lin et al, 2020), and oncogenesis (Ceci et al, 2021), to mention some. RNA secondary structures serve as binding platforms for the RNA-binding proteins, determine the assembly of ribonucleoprotein complexes and affect gene expression 2019; Sanchez de Groot et al, 2019) This is well illustrated by riboswitches and internal ribosome entry sites (IRESs) that control prokaryotic and eukaryotic/viral gene expression, respectively (Jackson et al, 2010; Serganov & Nudler, 2013). These regulatory elements are usually located in the 59 UTRs but RNA structures within the coding sequences can mediate translation. G4 structures in vitro using shorter RNA sequences show high thermostability (Arora & Maiti, 2009)
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