Polycomb repressive complex 2 binds RNA irrespective of stereochemistry

Abstract

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.