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標題: A general strategy to inhibiting viral -1 frameshifting based on upstream attenuation duplex formation
作者: Hu, Hao-Teng
Cho, Che-Pei
Lin, Ya-Hui
Chang, Kung-Yao
關鍵字: Cell Line;DNA;DNA, Antisense;Gene Expression Regulation, Viral;HEK293 Cells;Humans;Inverted Repeat Sequences;Middle East Respiratory Syndrome Coronavirus;RNA, Messenger;RNA, Viral;Ribosomes;Frameshifting, Ribosomal
Project: Nucleic acids research, Volume 44, Issue 1, Page(s) 256-66.
Viral -1 programmed ribosomal frameshifting (PRF) as a potential antiviral target has attracted interest because many human viral pathogens, including human immunodeficiency virus (HIV) and coronaviruses, rely on -1 PRF for optimal propagation. Efficient eukaryotic -1 PRF requires an optimally placed stimulator structure downstream of the frameshifting site and different strategies targeting viral -1 PRF stimulators have been developed. However, accessing particular -1 PRF stimulator information represents a bottle-neck in combating the emerging epidemic viral pathogens such as Middle East respiratory syndrome coronavirus (MERS-CoV). Recently, an RNA hairpin upstream of frameshifting site was shown to act as a cis-element to attenuate -1 PRF with mechanism unknown. Here, we show that an upstream duplex formed in-trans, by annealing an antisense to its complementary mRNA sequence upstream of frameshifting site, can replace an upstream hairpin to attenuate -1 PRF efficiently. This finding indicates that the formation of a proximal upstream duplex is the main determining factor responsible for -1 PRF attenuation and provides mechanistic insight. Additionally, the antisense-mediated upstream duplex approach downregulates -1 PRF stimulated by distinct -1 PRF stimulators, including those of MERS-CoV, suggesting its general application potential as a robust means to evaluating viral -1 PRF inhibition as soon as the sequence information of an emerging human coronavirus is available.
DOI: 10.1093/nar/gkv1307
Appears in Collections:生物化學研究所

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