RT Journal Article SR Electronic T1 Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors JF bioRxiv FD Cold Spring Harbor Laboratory SP 111138 DO 10.1101/111138 A1 Anton G. Henssen A1 Richard Koche A1 Jiali Zhuang A1 Eileen Jiang A1 Casie Reed A1 Amy Eisenberg A1 Eric Still A1 Ian C. MacArthur A1 Elias Rodríguez-Fos A1 Santiago Gonzalez A1 Montserrat Puiggròs A1 Andrew N. Blackford A1 Christopher E. Mason A1 Elisa de Stanchina A1 Mithat Gönen A1 Anne-Katrin Emde A1 Minita Shah A1 Kanika Arora A1 Catherine Reeves A1 Nicholas D. Socci A1 Elizabeth Perlman A1 Cristina R. Antonescu A1 Charles W. M. Roberts A1 Hanno Steen A1 Elizabeth Mullen A1 Stephen P. Jackson A1 David Torrents A1 Zhiping Weng A1 Scott A. Armstrong A1 Alex Kentsis YR 2017 UL http://biorxiv.org/content/early/2017/02/23/111138.abstract AB Genomic rearrangements are a hallmark of childhood solid tumors, but their mutational causes remain poorly understood. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as an enzymatically active human DNA transposase expressed in the majority of rhabdoid tumors, a lethal childhood cancer. Using assembly-based whole-genome DNA sequencing, we observed previously unknown somatic genomic rearrangements in primary human rhabdoid tumors. These rearrangements were characterized by deletions and inversions involving PGBD5-specific signal (PSS) sequences at their breakpoints, with some recurrently targeting tumor suppressor genes, leading to their inactivation. PGBD5 was found to be physically associated with human genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. We found that ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote penetrant cell transformation in vitro and in immunodeficient mice in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain, as well as end-joining DNA repair, and induced distinct structural rearrangements, involving PSS-associated breakpoints, similar to those found in primary human rhabdoid tumors. This defines PGBD5 as an oncogenic mutator and provides a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.