Published online 6 April 2004
Nucleic Acids Research, 2004, Vol. 32, No. 6 2039-2048
© 2004 Oxford University Press
An RNA secondary structure bias for non-homologous reverse transcriptase-mediated deletions in vivo
1 Department of Molecular Biology and 2 Department of Medical Microbiology and Immunology, University of Aarhus, C.F. Mollers Allé, Building 130, DK-8000 Aarhus, Denmark
*To whom correspondence should be addressed at Department of Molecular Biology, University of Aarhus, DK-8000 Aarhus, Denmark. Tel: +45 8 9421111, direct, +45 8 9422614; Fax: +45 8 6196500; Email: fsp{at}mb.au.dk
Present addresses:
Thomas Jespersen, Department of Medical Physiology, The Panum Institue, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N., Denmark
Lars Aagaard, Bioinformatics Research Center, Department of Computer Science, Aarhus University, DK-8000 Aarhus, Denmark
Received December 19, 2003; Revised February 18, 2004; Accepted March 9, 2004
Murine leukemia viruses harboring an internal ribosome entry site (IRES)-directed translational cassette are able to replicate, but undergo loss of heterologous sequences upon continued passage. While complete loss of heterologous sequences is favored when these are flanked by a direct repeat, deletion mutants with junction sites within the heterologous cassette may also be retrieved, in particular from vectors without flanking repeats. Such deletion mutants were here used to investigate determinants of reverse transcriptase-mediated non-homologous recombination. Based upon previous structural analysis the individual recombination sites within the IRES could be assigned to either base-paired or unpaired regions of RNA. This assignment showed a significant bias (P = 0.000082) towards recombination within unpaired regions of the IRES. We propose that the events observed in this in vivo system result from template switching during first-strand cDNA synthesis and that the choice of acceptor sites for non-homologous recombination are guided by non-paired regions. Our results may have implications for recombination events taking place within structured regions of retroviral RNA genomes, especially in the absence of longer stretches of sequence similarity.
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