Friend or Foe: The Potential of Transposable Element Tuning

Transposable elements (TEs) are mobile DNA sequences that can be cut or copied and reintegrated elsewhere into the genome. Long considered junk DNA, owing to their disruptive frolicking, TEs have instead been determined to be major contributors to disease, development, and evolution. The evolutionary arms race between TEs and the DNA modification systems that curb the damage of TE proliferation has created a delicate balance of TE regulation in our cells. However, this tight control of TE propagation loosens over the course of our lives. The deregulation of TEs has been associated with the onset of several developmental diseases and human cancers. On the other hand, increased TE activity in cancerous cells in blind mole rats has been shown to impart them with cancer resistance by inducing concerted cell death of diseased cells. The difference in these antithetical outcomes is the tuning of TE activity, demonstrating the importance of characterizing TE dynamics. The potential benefits are twofold: in the prevention of TE-associated diseases and the promise of developing TEs as genetic therapeutics for diseases such as cancers. In this study we characterize the dynamics of the autonomous TE, IS608. Several questions about IS608's transposition process have remained unanswered. Firstly, an unknown mechanism is employed to resolve the TE-complementary strand which may or may not result in TE replication. Secondly, IS608 contains a gene of unknown function, TnpB. We address these questions through real-time tracking of fluorescence-tagged genetic sequences, that allow us to measure transposase, TnpB protein and excision levels in live cells. We show that TnpB works with transposase to increase the active TE count, not through replication but through conservation of active TEs. We propose a model in which TnpB increases the efficiency of successful reinsertion of excised TEs. TnpB may achieve this by use of its RuvC-like domain to improve TE insertion.