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Molecular and Cellular Biology, February 2007, p. 1125-1132, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01899-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Human SETMAR Protein Preserves Most of the Activities of the Ancestral Hsmar1 Transposase ^,

Danxu Liu, Julien Bischerour, Azeem Siddique, Nicolas Buisine, Yves Bigot, and Ronald Chalmers^*

University of Oxford, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, United Kingdom

Received 8 October 2006/ Returned for modification 6 November 2006/ Accepted 10 November 2006

Transposons have contributed protein coding sequences to a unexpectedly large number of human genes. Except for the V(D)J recombinase and telomerase, all remain of unknown function. Here we investigate the activity of the human SETMAR protein, a highly expressed fusion between a histone H3 methylase and a mariner family transposase. Although SETMAR has demonstrated methylase activity and a DNA repair phenotype, its mode of action and the role of the transposase domain remain obscure. As a starting point to address this problem, we have dissected the activity of the transposase domain in the context of the full-length protein and the isolated transposase domain. Complete transposition of an engineered Hsmar1 transposon by the transposase domain was detected, although the extent of the reaction was limited by a severe defect for cleavage at the 3' ends of the element. Despite this problem, SETMAR retains robust activity for the other stages of the Hsmar1 transposition reaction, namely, site-specific DNA binding to the transposon ends, assembly of a paired-ends complex, cleavage of the 5' end of the element in Mn²⁺, and integration at a TA dinucleotide target site. SETMAR is unlikely to catalyze transposition in the human genome, although the nicking activity may have a role in the DNA repair phenotype. The key activity for the mariner domain is therefore the robust DNA-binding and looping activity which has a high potential for targeting the histone methylase domain to the many thousands of specific binding sites in the human genome provided by copies of the Hsmar1 transposon.

Published ahead of print on 27 November 2006.

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

These authors contributed equally to this work.

Present address: Laboratoire d'Etude des Parasites Génétiques, FRE CNRS 2969, Université François Rabelais, UFR des Sciences et Techniques, Parc Grandmont, Avenue monge, 37200 Tours, France.

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