Department of Chemistry, Texas A&M University, College Station, TX, USA.
Chem Commun (Camb). 2018 Oct 23;54(85):12061-12064. doi: 10.1039/c8cc07433j.
The Polycomb Repressive Complex 2 (PRC2) interacts promiscuously with G-quadruplex (G4) RNA structures. Herein, we tested the limit of this promiscuity by exploring the interaction of PRC2 with G4 RNAs comprised of l-ribonucleic acids (l-RNA), the enantiomer of naturally occurring d-RNA. Remarkably, we find that PRC2 binds similarly to both d- and l-G4 RNAs, suggesting that these interactions are independent of stereochemistry. Moreover, we show that d- and l-RNAs bind to the same site on PRC2, enabling l-G4 RNAs to outcompete native substrates for binding. This work challenges the prevailing assumption that l-oligonucleotides are "invisible" to native biology and provides a unique opportunity to develop a novel class of PRC2 inhibitors based on nuclease-resistant l-RNA.
多梳抑制复合物 2（PRC2）与 G-四链体（G4）RNA 结构广泛相互作用。在此，我们通过探索 PRC2 与由 l-核糖核酸（l-RNA）组成的 G4 RNA 的相互作用来测试这种混杂性的极限，l-RNA 是天然存在的 d-RNA 的对映体。值得注意的是，我们发现 PRC2 与 d-G4 RNA 和 l-G4 RNA 的结合相似，这表明这些相互作用不依赖于立体化学。此外，我们表明 d-RNA 和 l-RNA 结合到 PRC2 上的相同位点，使 l-G4 RNA 能够与天然底物竞争结合。这项工作挑战了 l-寡核苷酸对天然生物学“不可见”的普遍假设，并为开发基于耐核酸酶的 l-RNA 的新型 PRC2 抑制剂提供了独特的机会。
