Regulation of DENV replication by a coding region structural element

RNA cis-acting elements are often identified in the UTRs of cellular and viral messages, and several regions of the flavivirus 5' and 3' UTRs have been implicated in the regulation of viral translation and RNA synthesis (Alvarez et al 2005a, 2005b, Chiu et al 2005, Holden & Harris 2004, Holden et al 2006, Tilgner & Shi 2004). RNA regulatory elements located in the coding regions are less commonly identified. Using computer algorithms (e.g. RNAalfold), we found phylogenetic evidence that a capsid-coding region hairpin structure (cHP) is maintained among mosquito- and tick-borne flaviviruses (Clyde & Harris 2006). In mosquito-borne flaviviruses, the cHP is located 12—16 nucleotides downstream of the first AUG (Fig. 2A), which is in a poor initiation context. Through mutagenic analysis, we demonstrated that the DENV-2 cHP functions in start site selection in human hepatoma (Hep3B) and Ae. albopictus mosquito (C6/36) cells, directing first AUG usage proportional to its stability in a position-dependent and sequence-independent manner (Clyde & Harris 2006). This is consistent with a previously proposed mechanism whereby RNA secondary structure 12—15 nucleotides downstream of a start codon in a poor initiation context can enhance recognition of the suboptimal codon (Kozak 1989, 1990) by causing the scanning initiation machinery to pause at the structural element in order to unwind it, allowing the ribosome to remain in contact with a start codon in a poor initiation context (Kozak 1990, 1991).

plt22ps by D. Stewart and M. Zuker '2005 Washington University

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