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PGBD5 promotes site-specific oncogenic mutations in human tumors
Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489359/ https://www.ncbi.nlm.nih.gov/pubmed/28504702 http://dx.doi.org/10.1038/ng.3866 |
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author | Henssen, Anton G. Koche, Richard Zhuang, Jiali Jiang, Eileen Reed, Casie Eisenberg, Amy Still, Eric MacArthur, Ian C. Rodríguez-Fos, Elias Gonzalez, Santiago Puiggròs, Montserrat Blackford, Andrew N. Mason, Christopher E. de Stanchina, Elisa Gönen, Mithat Emde, Anne-Katrin Shah, Minita Arora, Kanika Reeves, Catherine Socci, Nicholas D. Perlman, Elizabeth Antonescu, Cristina R. Roberts, Charles W. M. Steen, Hanno Mullen, Elizabeth Jackson, Stephen P. Torrents, David Weng, Zhiping Armstrong, Scott A. Kentsis, Alex |
author_facet | Henssen, Anton G. Koche, Richard Zhuang, Jiali Jiang, Eileen Reed, Casie Eisenberg, Amy Still, Eric MacArthur, Ian C. Rodríguez-Fos, Elias Gonzalez, Santiago Puiggròs, Montserrat Blackford, Andrew N. Mason, Christopher E. de Stanchina, Elisa Gönen, Mithat Emde, Anne-Katrin Shah, Minita Arora, Kanika Reeves, Catherine Socci, Nicholas D. Perlman, Elizabeth Antonescu, Cristina R. Roberts, Charles W. M. Steen, Hanno Mullen, Elizabeth Jackson, Stephen P. Torrents, David Weng, Zhiping Armstrong, Scott A. Kentsis, Alex |
author_sort | Henssen, Anton G. |
collection | PubMed |
description | Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints, recurrently inactivating tumor suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain, as well as end-joining DNA repair, and induced structural rearrangements with PSS breakpoints. This defines PGBD5 as an oncogenic mutator and provides a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors. |
format | Online Article Text |
id | pubmed-5489359 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
record_format | MEDLINE/PubMed |
spelling | pubmed-54893592017-11-15 PGBD5 promotes site-specific oncogenic mutations in human tumors Henssen, Anton G. Koche, Richard Zhuang, Jiali Jiang, Eileen Reed, Casie Eisenberg, Amy Still, Eric MacArthur, Ian C. Rodríguez-Fos, Elias Gonzalez, Santiago Puiggròs, Montserrat Blackford, Andrew N. Mason, Christopher E. de Stanchina, Elisa Gönen, Mithat Emde, Anne-Katrin Shah, Minita Arora, Kanika Reeves, Catherine Socci, Nicholas D. Perlman, Elizabeth Antonescu, Cristina R. Roberts, Charles W. M. Steen, Hanno Mullen, Elizabeth Jackson, Stephen P. Torrents, David Weng, Zhiping Armstrong, Scott A. Kentsis, Alex Nat Genet Article Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints, recurrently inactivating tumor suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain, as well as end-joining DNA repair, and induced structural rearrangements with PSS breakpoints. This defines PGBD5 as an oncogenic mutator and provides a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors. 2017-05-15 2017-07 /pmc/articles/PMC5489359/ /pubmed/28504702 http://dx.doi.org/10.1038/ng.3866 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Henssen, Anton G. Koche, Richard Zhuang, Jiali Jiang, Eileen Reed, Casie Eisenberg, Amy Still, Eric MacArthur, Ian C. Rodríguez-Fos, Elias Gonzalez, Santiago Puiggròs, Montserrat Blackford, Andrew N. Mason, Christopher E. de Stanchina, Elisa Gönen, Mithat Emde, Anne-Katrin Shah, Minita Arora, Kanika Reeves, Catherine Socci, Nicholas D. Perlman, Elizabeth Antonescu, Cristina R. Roberts, Charles W. M. Steen, Hanno Mullen, Elizabeth Jackson, Stephen P. Torrents, David Weng, Zhiping Armstrong, Scott A. Kentsis, Alex PGBD5 promotes site-specific oncogenic mutations in human tumors |
title | PGBD5 promotes site-specific oncogenic mutations in human tumors |
title_full | PGBD5 promotes site-specific oncogenic mutations in human tumors |
title_fullStr | PGBD5 promotes site-specific oncogenic mutations in human tumors |
title_full_unstemmed | PGBD5 promotes site-specific oncogenic mutations in human tumors |
title_short | PGBD5 promotes site-specific oncogenic mutations in human tumors |
title_sort | pgbd5 promotes site-specific oncogenic mutations in human tumors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489359/ https://www.ncbi.nlm.nih.gov/pubmed/28504702 http://dx.doi.org/10.1038/ng.3866 |
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