A novel splice donor site in the GAG-POL gene is required for HIV-1 RNA stability

doi:10.1074/jbc.M513698200

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Papers In Press, published online ahead of print May 4, 2006
J. Biol. Chem, 10.1074/jbc.M513698200
Submitted on December 23, 2005
Accepted on May 4, 2006

A novel splice donor site in the GAG-POL gene is required for HIV-1 RNA stability

Martin Lützelberger, Line Sinnathamby Reinert, Atze T. Das, Ben Berkhout, and Jørgen Kjems

Dept. of Molecular Biology, Århus University, Århus C 8000

Corresponding Author: jk{at}mb.au.dk

Productive infection and successful replication of HIV-1 requires the balanced expression of all viral genes. This is achieved by a combination of alternative splicing events and regulated nuclear export of viral RNA. Since viral splicing is incomplete and intron-containing RNAs must be exported from the nucleus, where they are normally retained, it must be ensured that the unspliced HIV-1 RNA is actively exported from the nucleus and protected from degradation by processes such as nonsense-mediated decay (NMD). Here we report the identification of a novel 178 nt-long exon located in the gag-pol gene of HIV-1 and its inclusion in at least two different mRNA species. Although efficiently spliced in vitro, this exon appears to be tightly repressed and infrequently used in vivo. The splicing is activated or repressed in vitro by the splicing factors ASF/SF2 and hnRNP A1, respectively, suggesting that splicing is controlled by these factors. Interestingly, mutations in the 5’ splice-site resulted in a dramatic reduction in the steady-state level of HIV-1 RNA and this effect was partially reversed by expression of U1 snRNA harbouring the compensatory mutation. This implies that U1 snRNA binding to optimal but non-functional splice-sites might have a role in protecting unspliced HIV-1 mRNA from degradation.

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