A general strategy to inhibiting viral -1 frameshifting based on upstream attenuation duplex formation

Hu, Hao-Teng; Cho, Che-Pei; Lin, Ya-Hui; Chang, Kung-Yao

Reading-frame maintenance is crucial for translational fidelity because it ensures that codons are in the correct reading-frame of an mRNA on delivery into the A site of an elongating ribosome. However, functional translational frameshifting is programmed site-specifically into particu-lar mRNA of a variety of mobile elements as well as viruses and a few cellular genes (1) (2) (3) (4) (5) (6) (7) . Specifically programmed sequences and structures in mRNA can cause a fraction of elongating ribosomes to shift 1 nt in the 5 -direction of mRNA, leading to a −1 programmed reading-frame shift (PRF), whereas a +1 frameshifting occurs when the ribosome slips toward the 3 -direction by 1 nt (8) . In addition to the in-frame translation products, frameshifting events thus allow the synthesis of an extra protein with its N-terminal and C-terminal regions (separated by the shifting site) encoded by the 0-frame and the shifted frames, respectively. Many viruses require −1 frameshifting in their decoding of crucial viral genes and rely on −1 PRF efficiency to control the ratio between viral proteins for optimal viral propagation.