Genomic DNA transposition induced by human PGBD5

Abstract

Transposons are mobile genetic elements that are found in nearly all organisms, including humans. Mobilization of DNA transposons by transposase enzymes can cause genomic rearrangements, but our knowledge of human genes derived from transposases is limited. In this study, we find that the protein encoded by human PGBD5, the most evolutionarily conserved transposable element-derived gene in vertebrates, can induce stereotypical cut-and-paste DNA transposition in human cells. Genomic integration activity of PGBD5 requires distinct aspartic acid residues in its transposase domain, and specific DNA sequences containing inverted terminal repeats with similarity to piggyBac transposons. DNA transposition catalyzed by PGBD5 in human cells occurs genome-wide, with precise transposon excision and preference for insertion at TTAA sites. The apparent conservation of DNA transposition activity by PGBD5 suggests that genomic remodeling contributes to its biological function.DOI: http://dx.doi.org/10.7554/eLife.10565.001

Gene Therapy with the Sleeping Beauty Transposon System

“…Second, human cells do not express a protein with sufficient similarity to the SB transposase that could remobilize a genomically integrated SB vector. By contrast, the human PGBD5 transposase-derived protein can mobilize insect piggyBac (PB) transposon vectors in human cells [80]. Thus, despite the vast evolutionary distance between PGBD5 and insect PB transposons, there appears to be a cross-reaction between a catalytically active endogenous human transposase and transposon vector sequences that are exogenously delivered into human cells by gene transfer.…”

Endogenous Transposase Source in Human Cells Mobilizes piggyBac Transposons

“…Transposons can occasionally be recruited for useful functions by their hosts, and the human genome has five such "domesticated" genes derived from PB transposases. In a recent study, Henssen et al 1 examined one such gene product, PGBD5 (piggyBac-derived 5), with the goal of probing the potential of this protein to catalyze bona fide transposition. Very unexpectedly, the study shows that PGBD5 can mobilize the insect PB transposon in human cell culture.…”

“…Although the physiologically relevant, endogenous sites on which PGBD5 can potentially act are currently unknown, the human genome contains thousands of transposon-like sequences with sequence similarity to the ITRs of the T. ni PB transposon. 1 Thus, PGBD5 might be involved in a DNA recombination reaction involving such sites. On the basis of the expression pattern of PGBD5, it is tempting to speculate that, as with LINE-1 retrotransposition in the brain, 23 PGBD5-mediated DNA recombination may contribute to somatic mosaicism in the central nervous system.…”

“…21 PGBD5 encodes a putative fulllength transposase that is preferentially expressed in the early embryo and in the adult brain and central nervous system in vertebrates, including humans. 21 Henssen et al 1 set out to investigate whether PGBD5 is transpositionally active. They transfected human HEK293 cells with a transposon donor plasmid containing a neomycin resistance gene (neo)-tagged T. ni PB transposon and a helper plasmid expressing PGBD5.…”

Sleeping Beautytransposition: from biology to applications

“…Importantly, the SB transposase is highly specific with respect to the sequences that it can mobilize, and does not cross-mobilize related Tdr1 elements in the zebrafish genome (Ivics et al, 1997;. Surprisingly, by contrast, PGBD5 has been reported to be capable of mobilizing the insect-derived gene transfer tool, piggyBac (Henssen et al, 2015;Ivics, 2016).…”