期刊
MOLECULES
卷 20, 期 5, 页码 7602-7619出版社
MDPI
DOI: 10.3390/molecules20057602
关键词
RNAi; siRNA; single-stranded siRNA; L-threoninol; Ago2; RISC; silencing asymmetry; wobble base pair; on-; off-target effects; central mismatched siRNA
资金
- European Union (MULTIFUN) [NMP4-LA-2011-262943]
- Spanish Ministry of Education [CTQ2010-20541]
- Generalitat de Catalunya [2009/SGR/208]
- VI National R&D&i Plan, Iniciativa Ingenio, Consolider Program, CIBER Actions
- Instituto de Salud Carlos III
The understanding of the mechanisms behind nucleotide recognition by Argonaute 2, core protein of the RNA-induced silencing complex, is a key aspect in the optimization of small interfering RNAs (siRNAs) activity. To date, great efforts have been focused on the modification of certain regions of siRNA, such as the 3'/5'-termini and the seed region. Only a few reports have described the roles of central positions flanking the cleavage site during the silence process. In this study, we investigate the potential correlations between the thermodynamic and silencing properties of siRNA molecules carrying, at internal positions, an acyclic L-threoninol nucleic acid (aTNA) modification. Depending on position, the silencing is weakened or impaired. Furthermore, we evaluate the contribution of mismatches facing either a natural nucleotide or an aTNA modification to the siRNA potency. The position 11 of the antisense strand is more permissive to mismatches and aTNA modification, in respect to the position 10. Additionally, comparing the ON-/OFF-target silencing of central mismatched siRNAs with 5'-terminal modified siRNA, we concluded: (i) central perturbation of duplex pairing features weights more on potency rather than silencing asymmetry; (ii) complete bias for the ON-target silencing can be achieved with single L-threoninol modification near the 5'-end of the sense strand.
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