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Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors

Anton G. Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Ian C. MacArthur, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N. Blackford, Christopher E. Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D. Socci, Elizabeth Perlman, Cristina R. Antonescu, Charles W. M. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, View ORCID ProfileAlex Kentsis
doi: https://doi.org/10.1101/111138
Anton G. Henssen
1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Richard Koche
2Cancer Biology & Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Jiali Zhuang
3Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA,USA
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Eileen Jiang
1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Casie Reed
1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Amy Eisenberg
1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Eric Still
1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Ian C. MacArthur
1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Elias Rodríguez-Fos
4Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center (BSC-CNS), Barcelona,Spain
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Santiago Gonzalez
4Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center (BSC-CNS), Barcelona,Spain
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Montserrat Puiggròs
4Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center (BSC-CNS), Barcelona,Spain
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Andrew N. Blackford
5The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge,UK
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Christopher E. Mason
6Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY,USA
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Elisa de Stanchina
7Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Mithat Gönen
8Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065,USA
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Anne-Katrin Emde
9New York Genome Center, New York, NY,USA
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Minita Shah
9New York Genome Center, New York, NY,USA
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Kanika Arora
9New York Genome Center, New York, NY,USA
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Catherine Reeves
9New York Genome Center, New York, NY,USA
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Nicholas D. Socci
10Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY
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Elizabeth Perlman
11Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL,USA
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Cristina R. Antonescu
12Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Charles W. M. Roberts
13Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN,USA
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Hanno Steen
14Department of Pathology, Boston Children's Hospital, Boston, MA,USA
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Elizabeth Mullen
15Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA,USA
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Stephen P. Jackson
5The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge,UK
16Department of Biochemistry, University of Cambridge, Cambridge,UK
17The Wellcome Trust Sanger Institute, Hinxton, Cambridge,UK
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David Torrents
4Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center (BSC-CNS), Barcelona,Spain
18InstitucióCatalana de Recerca i EstudisAvangats (ICREA), Barcelona,Spain
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Zhiping Weng
3Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA,USA
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Scott A. Armstrong
2Cancer Biology & Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY,USA
19Weill Cornell Medical College, Cornell University, New York, NY,USA
20Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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Alex Kentsis
1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY,USA
19Weill Cornell Medical College, Cornell University, New York, NY,USA
20Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY,USA
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  • ORCID record for Alex Kentsis
  • For correspondence: kentsisresearchgroup@gmail.com
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Abstract

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.

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Posted February 23, 2017.
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Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors
Anton G. Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Ian C. MacArthur, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N. Blackford, Christopher E. Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D. Socci, Elizabeth Perlman, Cristina R. Antonescu, Charles W. M. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, Alex Kentsis
bioRxiv 111138; doi: https://doi.org/10.1101/111138
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Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors
Anton G. Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Ian C. MacArthur, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N. Blackford, Christopher E. Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D. Socci, Elizabeth Perlman, Cristina R. Antonescu, Charles W. M. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, Alex Kentsis
bioRxiv 111138; doi: https://doi.org/10.1101/111138

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