PGBD5 promotes site-specific oncogenic mutations in human tumors

Nature Genetics
Anton G HenssenAlex Kentsis

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.

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Citations

Jun 29, 2017·Nature Genetics·Stephen C MackMichael D Taylor
Feb 13, 2018·The Journal of Pathology·Sarah WatsonFranck Tirode
Sep 19, 2019·The Plant Journal : for Cell and Molecular Biology·Jie ZhangYong Xu
Nov 8, 2018·Scientific Reports·Anthony R ColomboGiridharan Ramsingh
Nov 3, 2017·Science Translational Medicine·Anton G HenssenAlex Kentsis
Mar 5, 2020·Neuro-oncology·Lindsey M HoffmanAnnie Huang
May 12, 2020·Pediatric Blood & Cancer·Alex Kentsis
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Aug 25, 2021·PLoS Biology·Yi Feng, Laura F Landweber

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Methods Mentioned

BETA
Illumina sequencing
PCR
immunoprecipitation
xenografts
Protein blot
fluorescence-activated cell sorting
xenograft
ChIP

Software Mentioned

Pannoramic Viewer
ENSEMBL
LoFreq
TARGET Data Matrix
SplazerS
GATK
BWA MEM
MuTect
SMuFin
MACS

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