Poly(A) Tail Recognition by a Viral RNA Element Through Assembly of a Triple Helix

Self-Protection Mechanism Kaposi's sarcoma–associated herpesvirus (KSHV) causes an AIDS-associated cancer. During its lytic phase, the virus produces a noncoding polyadenylated nuclear RNA that accumulates to high levels in infected cells. This occurs because a helix-loop-helix element, called ENE within the RNA, that contains a uridine-rich internal loop, sequesters the poly(A) tail, preventing the initiation of RNA decay. Mitton-Fry et al. (p. 1244) have determined the 2.5 angstrom structure of the ENE core bound to the RNA. Instead of just binding to the uridine-rich loop, as was expected, the poly(A) tail interacts with the loop and lower stem to form a triple helix to prevent decay. Similar mechanisms may protect other noncoding RNAs from rapid turnover. A hairpin structure within a viral noncoding RNA protects its poly(A) tail from degradation. Kaposi’s sarcoma–associated herpesvirus produces a highly abundant, nuclear noncoding RNA, polyadenylated nuclear (PAN) RNA, which contains an element that prevents its decay. The 79-nucleotide expression and nuclear retention element (ENE) was proposed to adopt a secondary structure like that of a box H/ACA small nucleolar RNA (snoRNA), with a U-rich internal loop that hybridizes to and protects the PAN RNA poly(A) tail. The crystal structure of a complex between the 40-nucleotide ENE core and oligo(A)9 RNA at 2.5 angstrom resolution reveals that unlike snoRNAs, the U-rich loop of the ENE engages its target through formation of a major-groove triple helix. A-minor interactions extend the binding interface. Deadenylation assays confirm the functional importance of the triple helix. Thus, the ENE acts as an intramolecular RNA clamp, sequestering the PAN poly(A) tail and preventing the initiation of RNA decay.