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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
The unusual structure of the PiggyMac cysteine-rich domain reveals zinc finger diversity in PiggyBac-related transposases
Mobile DNA Open Access 29 April 2021
Nature Communications Open Access 10 July 2020
Nature Communications Open Access 03 January 2020
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
Alexandrov, L.B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Weinstein, J.N. et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).
Futreal, P.A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).
Huether, R. et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat. Commun. 5, 3630 (2014).
Northcott, P.A. et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511, 428–434 (2014).
Mansour, M.R. et al. Oncogene regulation: an oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346, 1373–1377 (2014).
Molenaar, J.J. et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483, 589–593 (2012).
Johann, P.D. et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29, 379–393 (2016).
Chun, H.J. et al. Genome-wide profiles of extra-cranial malignant rhabdoid tumors reveal heterogeneity and dysregulated developmental pathways. Cancer Cell 29, 394–406 (2016).
Jones, D.T. et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 488, 100–105 (2012).
Fischer, H.P., Thomsen, H., Altmannsberger, M. & Bertram, U. Malignant rhabdoid tumour of the kidney expressing neurofilament proteins: immunohistochemical findings and histogenetic aspects. Pathol. Res. Pract. 184, 541–547 (1989).
Lee, R.S. et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J. Clin. Invest. 122, 2983–2988 (2012).
van den Heuvel-Eibrink, M.M. et al. Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: a report of the SIOP renal tumour study group. Pediatr. Blood Cancer 56, 733–737 (2011).
Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).
Roberts, C.W., Leroux, M.M., Fleming, M.D. & Orkin, S.H. Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell 2, 415–425 (2002).
Rousseau-Merck, M.F., Fiette, L., Klochendler-Yeivin, A., Delattre, O. & Aurias, A. Chromosome mechanisms and INI1 inactivation in human and mouse rhabdoid tumors. Cancer Genet. Cytogenet. 157, 127–133 (2005).
Takita, J. et al. Genome-wide approach to identify second gene targets for malignant rhabdoid tumors using high-density oligonucleotide microarrays. Cancer Sci. 105, 258–264 (2014).
Smit, A.F. Interspersed repeats and other mementos of transposable elements in mammalian genomes. Curr. Opin. Genet. Dev. 9, 657–663 (1999).
Kazazian, H.H. Jr. Mobile elements: drivers of genome evolution. Science 303, 1626–1632 (2004).
Rodić, N. et al. Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma. Nat. Med. 21, 1060–1064 (2015).
Muotri, A.R. et al. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435, 903–910 (2005).
Shaheen, M., Williamson, E., Nickoloff, J., Lee, S.H. & Hromas, R. Metnase/SETMAR: a domesticated primate transposase that enhances DNA repair, replication, and decatenation. Genetica 138, 559–566 (2010).
Hiom, K., Melek, M. & Gellert, M. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 94, 463–470 (1998).
Navarro, J.M. et al. Site- and allele-specific polycomb dysregulation in T-cell leukaemia. Nat. Commun. 6, 6094 (2015).
Papaemmanuil, E. et al. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat. Genet. 46, 116–125 (2014).
Halper-Stromberg, E. et al. Fine mapping of V(D)J recombinase mediated rearrangements in human lymphoid malignancies. BMC Genomics 14, 565 (2013).
Dreyer, W.J., Gray, W.R. & Hood, L. The genetics, molecular, and cellular basis of antibody formation: some facts and a unifying hypothesis. Cold Spring Harb. Symp. Quant. Biol. 32, 353–367 (1967).
Majumdar, S., Singh, A. & Rio, D.C. The human THAP9 gene encodes an active P-element DNA transposase. Science 339, 446–448 (2013).
Henssen, A.G. et al. Genomic DNA transposition induced by human PGBD5. eLife 4, e10565 (2015).
Pavelitz, T., Gray, L.T., Padilla, S.L., Bailey, A.D. & Weiner, A.M. PGBD5: a neural-specific intron-containing piggyBac transposase domesticated over 500 million years ago and conserved from cephalochordates to humans. Mob. DNA 4, 23 (2013).
Henssen, A.G. et al. Forward genetic screen of human transposase genomic rearrangements. BMC Genomics 17, 548 (2016).
Zhuang, J. & Weng, Z. Local sequence assembly reveals a high-resolution profile of somatic structural variations in 97 cancer genomes. Nucleic Acids Res. 43, 8146–8156 (2015).
Moncunill, V. et al. Comprehensive characterization of complex structural variations in cancer by directly comparing genome sequence reads. Nat. Biotechnol. 32, 1106–1112 (2014).
Bralten, L.B. et al. The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma. Oncogene 29, 6138–6148 (2010).
Hahn, W.C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999).
Landree, M.A., Wibbenmeyer, J.A. & Roth, D.B. Mutational analysis of RAG1 and RAG2 identifies three catalytic amino acids in RAG1 critical for both cleavage steps of V(D)J recombination. Genes Dev. 13, 3059–3069 (1999).
Lu, C.P., Posey, J.E. & Roth, D.B. Understanding how the V(D)J recombinase catalyzes transesterification: distinctions between DNA cleavage and transposition. Nucleic Acids Res. 36, 2864–2873 (2008).
Gellert, M. V(D)J recombination: RAG proteins, repair factors, and regulation. Annu. Rev. Biochem. 71, 101–132 (2002).
Mitra, R., Fain-Thornton, J. & Craig, N.L. piggyBac can bypass DNA synthesis during cut and paste transposition. EMBO J. 27, 1097–1109 (2008).
Ochi, T. et al. DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 347, 185–188 (2015).
Aldaz, C.M., Ferguson, B.W. & Abba, M.C. WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochim. Biophys. Acta 1846, 188–200 (2014).
McClintock, B. The origin and behavior of mutable loci in maize. Proc. Natl. Acad. Sci. USA 36, 344–355 (1950).
Torchia, J. et al. Integrated (epi)-genomic analyses identify subgroup-specific therapeutic targets in CNS rhabdoid tumors. Cancer Cell 30, 891–908 (2016).
Li, X. et al. piggyBac transposase tools for genome engineering. Proc. Natl. Acad. Sci. USA 110, E2279–E2287 (2013).
Westbrook, T.F., Stegmeier, F. & Elledge, S.J. Dissecting cancer pathways and vulnerabilities with RNAi. Cold Spring Harb. Symp. Quant. Biol. 70, 435–444 (2005).
Ferguson, B.W. et al. The cancer gene WWOX behaves as an inhibitor of SMAD3 transcriptional activity via direct binding. BMC Cancer 13, 593 (2013).
Kentsis, A. et al. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat. Med. 18, 1118–1122 (2012).
Fox, R. & Aubert, M. Flow cytometric detection of activated caspase-3. Methods Mol. Biol. 414, 47–56 (2008).
Sordet, O. et al. Specific involvement of caspases in the differentiation of monocytes into macrophages. Blood 100, 4446–4453 (2002).
Yarilin, D. et al. Machine-based method for multiplex in situ molecular characterization of tissues by immunofluorescence detection. Sci. Rep. 5, 9534 (2015).
Fujisawa, S., Turkekul, M., Barlas, A., Fan, N. & Manova, K. Double in situ detection of sonic hedgehog mRNA and pMAPK protein in examining the cell proliferation signaling pathway in mouse embryo. Methods Mol. Biol. 717, 257–276 (2011).
Henssen, A., Carson, J.R. & Kentsis, A. Transposon mapping using flanking sequence exponential anchored (FLEA) PCR. Protocol Exchange http://dx.doi.org/10.1038/protex.2015.071 (2015).
Krivtsov, A.V. et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 14, 355–368 (2008).
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).
Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).
Wilm, A. et al. LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets. Nucleic Acids Res. 40, 11189–11201 (2012).
Saunders, C.T. et al. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics 28, 1811–1817 (2012).
Ye, K., Schulz, M.H., Long, Q., Apweiler, R. & Ning, Z. Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 25, 2865–2871 (2009).
Narzisi, G. et al. Accurate de novo and transmitted indel detection in exome-capture data using microassembly. Nat. Methods 11, 1033–1036 (2014).
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6, 80–92 (2012).
Xi, R. et al. Copy number variation detection in whole-genome sequencing data using the Bayesian information criterion. Proc. Natl. Acad. Sci. USA 108, E1128–E1136 (2011).
Rausch, T. et al. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics 28, i333–i339 (2012).
Wang, J. et al. CREST maps somatic structural variation in cancer genomes with base-pair resolution. Nat. Methods 8, 652–654 (2011).
Chen, K. et al. BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nat. Methods 6, 677–681 (2009).
Quinlan, A.R. & Hall, I.M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).
Emde, A.K. et al. Detecting genomic indel variants with exact breakpoints in single- and paired-end sequencing data using SplazerS. Bioinformatics 28, 619–627 (2012).
Krzywinski, M. et al. Circos: an information aesthetic for comparative genomics. Genome Res. 19, 1639–1645 (2009).
Grant, C.E., Bailey, T.L. & Noble, W.S. FIMO: scanning for occurrences of a given motif. Bioinformatics 27, 1017–1018 (2011).
Bailey, T.L. et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 37, W202–W208 (2009).
Hothorn, T., Bretz, F. & Westfall, P. Simultaneous inference in general parametric models. Biom. J. 50, 346–363 (2008).
Dunnett, C.W. & Tamhane, A.C. Step-down multiple tests for comparing treatments with a control in unbalanced one-way layouts. Stat. Med. 10, 939–947 (1991).
R Development Core Team R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2013).
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.
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 1 PGBD5 is highly expressed in rhabdoid and other pediatric and childhood solid tumors.
(a) Bar graph showing relative expression of PGBD5 in tumors (red), as compared to normal tissues (blue). Median expression is indicated by horizontal line, boxes indicate 25% and 75% quartiles; whiskers indicate minimum and maximum values. (b) Dot plot showing the relative PGBD5 mRNA expression in atypical teratoid/rhabdoid tumor (ATRT) molecular subgroups (SHH, Sonic hedgehog pathway activation; TYR, tyrosinase overexpression; MYC, MYC and HOX overexpression). Bars denote mean. (c) Dot plot showing the relative PGBD5 mRNA expression in medulloblastoma tumor molecular subgroups. (d) Dot plot showing the relative PGBD5 mRNA expression in ependymoma tumor molecular subgroups. (e) Dot plot showing the relative PGBD5 mRNA expression in ATRT tumors relative to the age of patients at diagnosis. Bars denote mean.
Sequence logos detected near the breakpoints of genomic rearrangements in the HPRT1 forward genetic screen (top)32, as compared to those observed in primary rhabdoid (middle) and engineered RPE cell tumors (bottom).
Supplementary Figure 3 Distribution and structure of somatic genomic rearrangements in primary rhabdoid tumors.
(a) Distribution of somatic deletions, duplications, insertions, inversions and translocations observed in 31 primary rhabdoid tumors. (b) Distribution of predicted mechanisms at the rearrangement breakpoints as homologous recombination (HR), microhomology-mediated end joining (MMEJ), mobile element rearrangements (ME), and non-template insertions (NI). (c) Tile plot showing recurrence of somatic translocations (blue), deletions (red), duplications (light blue), and inversions (green) affecting specific genes, excluding SMARCB1, in individual rhabdoid tumor specimens. (d) Validation of specific somatic rearrangements of TENM3 and CNTNAP2 genes, as assessed using variant and wild-type allele-specific PCR in matched tumor and normal primary patient specimens. (e-h) Schematics of gene structure of CNTNAP2 and TENM3 before and after rearrangements, and Sanger DNA sequencing chromatograms of the individual rearrangement breakpoints detected by variant allele-specific PCR in individual primary rhabdoid tumor specimens (arrowheads mark the breakpoints). (i) Validation of t(5;22) translocation using variant and allele-specific PCR. (j) Schematic of the chromosomes 5 and 22 before and after rearrangement, leading to the translocation breakpoint detected by variant allele-specific PCR (arrowhead marks the breakpoint).
Supplementary Figure 4 Schematic of flanking-sequence exponential anchored polymerase chain reaction (FLEA PCR).
Biotinylated primer specific for the NeoR cassette is used for linear extension, followed by streptavidin purification, and nested PCR to amplify integration breakpoints, followed by DNA sequencing.
Supplementary Figure 5 Ectopic expression of PGBD5 transforms immortalized BJ and RPE cells in vivo.
(a) Tumor volume as a function of time of RPE (right) and BJ cells (left) stably expressing GFP-PGBD5 and GFP only, compared to non-transduced cells and cells expressing SV40 large T antigen (LTA) and HRAS (n = 10 per group). (b) Kaplan-Meier analysis of tumor-free survival of mice with subcutaneous xenografts of RPE and BJ cells expressing GFP-PGBD5 or GFP only, as compared to non-transduced cells or cells expressing SV40 LTA and HRAS (n = 10 per group, P < 0.0001 by log-rank test).
Representative karyotype of BJ (lower panel) and RPE cells (upper panel) stably expressing GFP-PGBD5 (right) and GFP (left).
Supplementary Figure 7 Doxycycline-inducible PGBD5 expression in RPE cells leads to penetrant subcutaneous tumor formation in xenograft models.
(a) GFP-T. ni piggyBac is expressed at similar relative mRNA levels as GFP-PGBD5 in RPE cells as measured by quantitative RT-PCR (n = 3, P = 0.79 for GFP-PGBD5 vs. GFP-T. ni piggyBac). (b) Western blot against PGBD5 showing inducible expression of PGBD5 protein in RPE cells stably transduced with pINDUCER21-PGBD5 after 48 h of treatment with doxycycline (0-600 ng/mL) compared to RPE cells stably expressing GFP-PGBD5. (c) Tumor size of RPE xenografts as a function of time, with PGBD5 expression induced using doxycycline (+/- Dox) in RPE cells stably transduced with pINDUCER21-PGBD5 compared to GFP-PGBD5 expressing RPE cells and non-transduced cells. Cells were treated with doxycycline for 10 days prior to subcutaneous injection (n = 10 per group).
(a) Flow cytometric analysis of cleaved caspase-3 expression in PAXX+/+ and PAXX−/− RPE cells before and after 48 h of doxycycline-induced PGBD5 expression (500 ng/ml doxycycline). (b) Representative images of PAXX+/+ and PAXX−/− RPE cells stained for DAPI (blue) and γ-H2AX (red) 3 h, 6 h, 24 h and 30 h after doxycycline-induced PGBD5 expression (500 ng/ml doxycycline, scale bar = 50 μm). (c) Number of viable PAXX+/+ and PAXX−/− RPE cells per cm2 in monolayer culture as measured by trypan blue staining after 72 h of doxycycline-induced expression of PGBD5, as compared to untreated control cells (n = 3). *P = 1.52 x 10-4 for PAXX−/−; +Dox vs. PAXX−/−; -Dox. Error bars represent standard deviations of three independent experiments. (d) Fraction of γ-H2AX-positive cells over time in PAXX+/+ and PAXX−/− RPE cells before and after doxycycline-induced PGBD5 expression (500 ng/ml doxycycline, n = 3 per group).
Supplementary Figure 9 Conventional alignment-based variant analysis of structural variants in PGBD5-transformed RPE cells.
(a) Venn diagrams showing the number of identified SNVs and indels detected by Strelka, LoFreq and Pindel in genomes of RPE cells expressing GFP-PGBD5 compared to GFP. (b) Venn diagrams showing the number of identified exonic SNVs and indels detected by Strelka, loFreq and Pindel in GFP-PGBD5 expressing RPE cells. (c) Venn diagrams showing the number of identified large structural variants detected by DELLY, BreakDancer (BD) and CREST (filtered high-confidence set) in GFP-PGBD5 expressing RPE cells.
Supplementary Figure 10 GFP-PGBD5-expressing cells exhibit a low frequency of copy-number variants across the genome.
(a) Copy number profile in RPE cells expressing GFP-PGBD5 compared to GFP expressing cells, computed by BIC-Seq2. (b) Relative chromosomal sequence coverage in GFP-PGBD5 expressing cells (left) compared to GFP expressing cells (right) as a function of chromosome number.
Supplementary Figure 11 Single-nucleotide-variant mutational signatures of GFP-PGBD5-expressing cells.
(a) Fraction of SNVs involving each nucleotide in GFP-PGBD5 expressing RPE cells compared to GFP expressing cells as detected by Mutect, LoFreq and Strelka (left to right). (b) Mutational signature in GFP-PGBD5 expressing RPE cells measured as the relative fraction of SNVs (union of Mutect, LoFreq and Strelka) in each substitution class and sequence context immediately 3′ and 5′ to the mutated base. (c) Genomic distribution of SNVs in GFP-PGBD5 expressing RPE cells according to their mutational class (upper panel) and variant allele frequency (lower panel).
Supplementary Figure 12 PGBD5-induced genomic rearrangements in RPE cells and primary malignant rhabdoid tumors.
(a) Histogram showing the genomic size distribution of deletions (excluding small indels) detected by SMuFin in PGBD5-transformed RPE cells. (b) Distribution of somatic deletions, duplications, insertions, inversions and translocations observed in PGBD5-expressing RPE cell tumors. (c) Distribution of predicted mechanisms at the rearrangement breakpoints as homologous recombination (HR), microhomology-mediated end joining (MMEJ), mobile element rearrangements (ME), and non-template insertions (NI). (d) Variant allele-specific PCR of genomic rearrangements detected in PGBD5-expressing RPE cell tumors of RMST (#1), WWOX (#2), FHOD3 (#3), XRN2 (#4), and SERINC5 (#5). (e-h) Schematics of gene structure of RMST, WWOX, FHOD3, and SERINC5 genes before and after rearrangements, and Sanger DNA sequencing chromatograms of the individual rearrangement breakpoints detected by variant allele-specific PCR in individual primary RPE cell tumor specimens (arrowheads mark the breakpoints).
Supplementary Figure 13 Inactivation of WWOX is necessary but not sufficient for clonogenic maintenance of PGBD5-transformed RPE tumor cells.
(a) Western blot of WWOX showing shRNA-mediated depletion of WWOX in RPE-GFP cells stably transduced with pGIPZ-shWWOX, as compared to pGIPZ-shScramble control. Actin serves as loading control. (b,c) Representative photographs of Crystal violet-stained colonies (b) and clonogenic efficiency (c) of RPE-GFP cells expressing pGIPZ-shWWOX, as compared to pGIPZ-shScramble control. (P = 0.44). (d) Western blot of WWOX showing doxyclycline-induced expression of wild-type WWOX in RPE-GFP cells stably transduced with tetOn-advanced-WWOX vector, as compared to RPE-GFP-PGBD5 xenograft tumor-derived cells with PGBD5-induced WWOX mutation. (e,f) Representative photographs of Crystal violet-stained colonies (e) and clonogenic efficiency (f) of RPE-GFP cells and RPE-GFP-PGBD5 xenograft tumor-derived cells stably transduced with tetOn-advanced-WWOX and treated with doxycycline (500 ng/ml) or vehicle control. PGBD5-transformed cells with WWOX mutations, but not control GFP cells, exhibit significantly reduced clonogenic efficiency upon ectopic expression of wild-type WWOX (*P = 0.0098). Error bars represent standard deviations of three independent experiments.
(a) Schematic of intragenic deletion with the PSS sequences colored in red. (b) Schematic of possible mechanisms of PGBD5-induced rearrangements.
About this article
Cite this article
Henssen, A., Koche, R., Zhuang, J. et al. PGBD5 promotes site-specific oncogenic mutations in human tumors. Nat Genet 49, 1005–1014 (2017). https://doi.org/10.1038/ng.3866
Directed yeast genome evolution by controlled introduction of trans-chromosomic structural variations
Science China Life Sciences (2022)
The unusual structure of the PiggyMac cysteine-rich domain reveals zinc finger diversity in PiggyBac-related transposases
Mobile DNA (2021)
Nature Communications (2020)
Nature Communications (2020)
Journal of Neuro-Oncology (2020)