title: The human SETMAR protein preserves most of the activities of the ancestral Hsmar1 transposase.
abstract: 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 Mn(2+), 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.
authors.affiliation: University of Oxford, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Danxu
authors.initials: D
authors.lastname: Liu
authors.forename: Julien
authors.initials: J
authors.lastname: Bischerour
authors.forename: Azeem
authors.initials: A
authors.lastname: Siddique
authors.forename: Nicolas
authors.initials: N
authors.lastname: Buisine
authors.forename: Yves
authors.initials: Y
authors.lastname: Bigot
authors.forename: Ronald
authors.initials: R
authors.lastname: Chalmers
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004251:DNA Transposable Elements / Q000235:genetics*; D005091:Exons / Q000235:genetics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011496:Protein Methyltransferases; D017434:Protein Structure, Tertiary
chemical_list: D004251:DNA Transposable Elements; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C510450:SETMAR protein, human