PGBD5 promotes site-specific oncogenic mutations in human 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

doi:10.1038/ng.3866

PGBD5 promotes site-specific oncogenic mutations in human 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. SocciElizabeth Perlman, Cristina R. Antonescu, Charles W.M. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, Alex Kentsis^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

62 Scopus citations

Abstract

Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding 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 and recurrently inactivated 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. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.

Original language	English (US)
Pages (from-to)	1005-1014
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	7
DOIs	https://doi.org/10.1038/ng.3866
State	Published - Jul 1 2017

Funding

We are grateful to A. Gutierrez, M. Mansour, D. Bauer, T. Look, H. Zhu, C. Feschotte, M. Kharas, J. Petrini, and M. Gil Mir for critical discussions, and J. Gilbert for editorial advice. We thank T. Westbrook (Baylor College of Medicine) and M. Aldaz (MD Anderson Cancer Center) for materials. This work was supported by funding from NIH K08 CA160660, P30 CA008748, U54 OD020355, UL1 TR000457, P50 CA140146, Spanish Ministerio de Economía y Competitividad SAF2014-60293-R, Cancer Research UK, the Wellcome Trust, the Starr Cancer Consortium, the Burroughs Wellcome Fund, the Sarcoma Foundation of America, the Matthew Larson Foundation, the Josie Robertson Investigator Program, and the Rita Allen Foundation. A.G.H. is supported by the Berliner Krebsgesellschaft e.V. and the Berlin Institute of Health. A.K. is supported as a Damon Runyon-Richard Lumsden Foundation Clinical Investigator.

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Henssen, A. G., Koche, R., Zhuang, J., Jiang, E., Reed, C., Eisenberg, A., Still, E., Macarthur, I. C., Rodríguez-Fos, E., Gonzalez, S., Puiggròs, M., Blackford, A. N., Mason, C. E., De Stanchina, E., Gönen, M., Emde, A. K., Shah, M., Arora, K., Reeves, C., ... Kentsis, A. (2017). PGBD5 promotes site-specific oncogenic mutations in human tumors. Nature Genetics, 49(7), 1005-1014. https://doi.org/10.1038/ng.3866

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title = "PGBD5 promotes site-specific oncogenic mutations in human tumors",

abstract = "Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding 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 and recurrently inactivated 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. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.",

author = "Henssen, {Anton G.} and Richard Koche and Jiali Zhuang and Eileen Jiang and Casie Reed and Amy Eisenberg and Eric Still and Macarthur, {Ian C.} and Elias Rodr{\'i}guez-Fos and Santiago Gonzalez and Montserrat Puiggr{\`o}s and Blackford, {Andrew N.} and Mason, {Christopher E.} and {De Stanchina}, Elisa and Mithat G{\"o}nen and Emde, {Anne Katrin} and Minita Shah and Kanika Arora and Catherine Reeves and Socci, {Nicholas D.} and Elizabeth Perlman and Antonescu, {Cristina R.} and Roberts, {Charles W.M.} and Hanno Steen and Elizabeth Mullen and Jackson, {Stephen P.} and David Torrents and Zhiping Weng and Armstrong, {Scott A.} and Alex Kentsis",

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Henssen, AG, Koche, R, Zhuang, J, Jiang, E, Reed, C, Eisenberg, A, Still, E, Macarthur, IC, Rodríguez-Fos, E, Gonzalez, S, Puiggròs, M, Blackford, AN, Mason, CE, De Stanchina, E, Gönen, M, Emde, AK, Shah, M, Arora, K, Reeves, C, Socci, ND, Perlman, E, Antonescu, CR, Roberts, CWM, Steen, H, Mullen, E, Jackson, SP, Torrents, D, Weng, Z, Armstrong, SA & Kentsis, A 2017, 'PGBD5 promotes site-specific oncogenic mutations in human tumors', Nature Genetics, vol. 49, no. 7, pp. 1005-1014. https://doi.org/10.1038/ng.3866

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AU - Henssen, Anton G.

AU - Koche, Richard

AU - Zhuang, Jiali

AU - Jiang, Eileen

AU - Reed, Casie

AU - Eisenberg, Amy

AU - Still, Eric

AU - Macarthur, Ian C.

AU - Rodríguez-Fos, Elias

AU - Gonzalez, Santiago

AU - Puiggròs, Montserrat

AU - Blackford, Andrew N.

AU - Mason, Christopher E.

AU - De Stanchina, Elisa

AU - Gönen, Mithat

AU - Emde, Anne Katrin

AU - Shah, Minita

AU - Arora, Kanika

AU - Reeves, Catherine

AU - Socci, Nicholas D.

AU - Perlman, Elizabeth

AU - Antonescu, Cristina R.

AU - Roberts, Charles W.M.

AU - Steen, Hanno

AU - Mullen, Elizabeth

AU - Jackson, Stephen P.

AU - Torrents, David

AU - Weng, Zhiping

AU - Armstrong, Scott A.

AU - Kentsis, Alex

PY - 2017/7/1

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N2 - Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding 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 and recurrently inactivated 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. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.

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PGBD5 promotes site-specific oncogenic mutations in human tumors

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UN SDGs

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