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Molecular and Cellular Biology, February 2008, p. 1230-1239, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01502-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Retrotransposon Target Site Selection by Imitation of a Cellular Protein ^,

Troy L. Brady, Peter G. Fuerst, Robert A. Dick, Clarice Schmidt, and Daniel F. Voytas^*

Department of Genetics, Development, and Cell Biology, 1035A Roy J. Carver Co-Laboratory, Iowa State University, Ames, Iowa 50011

Received 8 August 2007/ Returned for modification 19 September 2007/ Accepted 27 November 2007

Mobile elements rely on cellular processes to replicate, and therefore, mobile element proteins frequently interact with a variety of cellular factors. The integrase (IN) encoded by the retrotransposon Ty5 interacts with the heterochromatin protein Sir4, and this interaction determines Ty5's preference to integrate into heterochromatin. We explored the hypothesis that Ty5's targeting mechanism arose by mimicking an interaction between Sir4 and another cellular protein(s). Mutational analyses defined the requirements for the IN-Sir4 interaction, providing criteria to screen for cellular analogues. Esc1, a protein associated with the inner nuclear membrane, interacted with the same domain of Sir4 as IN, and 75% of mutations that disrupted IN-Sir4 interactions also abrogated Esc1-Sir4 interactions. A small motif critical for recognizing Sir4 was identified in Esc1. The functional equivalency of this motif and the Sir4-interacting domain of IN was demonstrated by swapping these motifs and showing that the chimeric IN and Esc1 proteins effectively target integration and partition DNA, respectively. We conclude that Ty5 targets integration by imitating the Esc1-Sir4 interaction and suggest molecular mimicry as a general mechanism that enables mobile elements to interface with cellular processes.

Published ahead of print on 17 December 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Microbiology, University of Pennsylvania School of Medicine, 402 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104.

Present address: The Jackson Laboratory, Burgess Research Group, Bar Harbor, ME 04609.