Discovery and protein language model-guided design of hyperactive transposases.

Ivančić, Dimitrije; Agudelo, Alejandro; Lindstrom-Vautrin, Jonathan; Jaraba-Wallace, Jessica; Gallo, Maria; Das, Ravi; Ragel, Alejandro; Herrero-Vicente, Jorge et al. · Nat Biotechnol · 2025

basic_science · Level V

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Abstract

The diversity and biochemical potential of the PiggyBac transposase gene insertion system remains largely unexplored. Using a eukaryotic transposon mining pipeline, we expand the explored diversity by two orders of magnitude and experimentally validate a subset of highly divergent PiggyBac sequences. Fine-tuning a protein language model to further expand PiggyBac sequence space discovers transposases with improved activity and that are compatible with T cell engineering and Cas9-directed transposase-assisted integration.