Over-production Inhibition

Certain transposons appear to be subject to a mode of regulation known as over-expression inhibition. This was first observed with the eukaryotic transposons Tc1/mariner Lampe (Lampe et al., 1998)(Lohe & Hartl, 1996, Hartl et al., 1997) where increasing the concentration of transposase results in a reduction in the level of transposition. It was subsequently observed with the sleeping beauty transposon (Geurts et al., 2003) (Zayed, et al., 2004). It also occurs in vivo in mice (Karsi, et al., 2001)(Mikkelsen, et al., 2003).

The biological rational for this is that "infection" of a naïve cell by the transposon results in a burst of transposition which is then attenuated by overproduction inhibition. This is then followed by gradual decay of the transposon.

The Chalmers lab (Claeys Bouuaert, et al., 2013) has provided an interesting and compelling explanation of this effect. Using the mariner family transposon Hsmar1 they present convincing data implying that overproduction inhibition occurs during transpososome assembly and is due to a combination of the multimeric state of the transposase coupled with competition for transposase binding sites at the Hsmar1 ends (Bouuaert, et al., 2014, Tellier, et al., 2015). The model (assembly-site-occlusion model) is based on the presence of transposase multimers (dimers) to the exclusion of monomers, in other words, end-binding required a dimeric transposase. At low transposase/transposon ratios, one dimer can bind both transposon ends resulting in the ordered assembly of the transpososome. An increase in the transposase dimer/transposon ratio results in binding of dimers to both transposon ends, preventing transpososome assembly. The model not only explains the in vivo transposase dose-response for Hsmar1 but also for the related Sleeping Beauty (SB) and piggyBac (PB) transposons. As yet, no information is at present available concerning the relevance of this mode of regulation to prokaryotic transposable elements.

References :

• Bouuaert CC, Tellier M & Chalmers R (2014) One to rule them all: A highly conserved motif in mariner transposase controls multiple steps of transposition. Mob Genet Elements 4: e28807.
• Claeys Bouuaert C, Lipkow K, Andrews SS, Liu D & Chalmers R (2013) The autoregulation of a eukaryotic DNA transposon.Elife 2: e00668.
• Geurts AM, Yang Y, Clark KJ, et al.(2003) Gene transfer into genomes of human cells by the sleeping beauty transposon system. Mol Ther 8: 108-117.
• Hartl DL, Lozovskaya ER, Nurminsky DI & Lohe AR (1997) What restricts the activity of mariner-like transposable elements. Trends.Genet. 13: 197-201.
• Karsi A, Moav B, Hackett P & Liu Z (2001) Effects of insert size on transposition efficiency of the sleeping beauty transposon in mouse cells. Mar Biotechnol (NY) 3: 241-245.
• Lampe DJ, Grant TE & Robertson HM (1998) Factors Affecting Transposition of the Himar1 mariner Transposon in Vitro. Genetics 149: 179-187.
• Lohe A & Hartl D (1996) Autoregulation of mariner transposase activity by overproduction and dominant-negative complementation. Mol Biol Evol 13: 549-555.
• Mikkelsen JG, Yant SR, Meuse L, Huang Z, Xu H & Kay MA (2003) Helper-Independent Sleeping Beauty transposon-transposase vectors for efficient nonviral gene delivery and persistent gene expression in vivo. Mol Ther 8: 654-665.
• Tellier M, Bouuaert CC & Chalmers R (2015) Mariner and the ITm Superfamily of Transposons. Microbiol Spectr 3: MDNA3-0033-2014.
• Zayed H, Izsvak Z, Walisko O & Ivics Z (2004) Development of hyperactive sleeping beauty transposon vectors by mutational analysis. Mol Ther 9: 292-304.