PGBD5 promotes site-specific oncogenic mutations in human tumors

Item Type:

Article

Title:

Creators Name:

Henssen, A.G. and Koche, R. and Zhuang, J. and Jiang, E. and Reed, C. and Eisenberg, A. and Still, E. and MacArthur, I.C. and Rodriguez-Fos, E. and Gonzalez, S. and Puiggròs, M. and Blackford, A.N. and Mason, C.E. and de Stanchina, E. and Gönen, M. and Emde, A.K. and Shah, M. and Arora, K. and Reeves, C. and Socci, N.D. and Perlman, E. and Antonescu, C.R. and Roberts, C.W.M. and Steen, H. and Mullen, E. and Jackson, S.P. and Torrents, D. and Weng, Z. and Armstrong, S.A. and Kentsis, A.

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.

Keywords:

Catalytic Domain, Cell Line, Chromosome Aberrations, Chromosome Breakpoints, DNA End-Joining Repair, Gene Rearrangement, Neoplasm DNA, Neoplastic Cell Transformation, Nucleic Acid Regulatory Sequences, Nude Mice, Recombinant Proteins, Rhabdoid Tumor, RNA Interference, Site-Directed Mutagenesis, Terminal Repeat Sequences, Transposases, Tumor Suppressor Genes, Animals, Mice

Source:

Nature Genetics

ISSN:

1061-4036

Publisher:

Nature Publishing Group

Volume:

Number:

Page Range:

1005-1014

Date:

July 2017

Additional Information:

Erratum in: Nat Genet 49(10):1558. Author Correction in: Nat Genet 52(11), 1265.

Official Publication:

https://doi.org/10.1038/ng.3866

PubMed:

View item in PubMed

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URL	URL Type
https://edoc.mdc-berlin.de/18409/	Preprint version

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